See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/326782966

Interleukin-34, a comprehensive review

Article  in  Journal of leukocyte biology · August 2018

DOI: 10.1002/JLB.MR1117-457R

CITATIONS READS

4 186

7 authors, including:

Muhammad Baghdadi Takuto Kobayashi

Hokkaido University Hokkaido University
30 PUBLICATIONS   559 CITATIONS    3 PUBLICATIONS   7 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Interleukin-34 & Cancer View project

All content following this page was uploaded by Muhammad Baghdadi on 06 August 2018.

The user has requested enhancement of the downloaded file.

DOI: 10.1002/JLB.MR1117-457R

REVIEW

Interleukin-34, a comprehensive review

Muhammad Baghdadi Yui Umeyama Naoki Hama Takuto Kobayashi
Nanumi Han Haruka Wada Ken-ichiro Seino

Division of Immunobiology, Institute for Genetic

Medicine, Hokkaido University, Sapporo, Japan
Correspondence
Muhammad Baghdadi (M.D., Ph.D.) and
Ken-ichiro Seino (M.D., Ph.D.), Division of
Immunobiology, Institute for Genetic Medicine,
Hokkaido University, Kita-15, Nishi-7, Kita-ku,
Sapporo 060–0815 Japan.
Email: Muhammad Baghdadi:
drmhb@igm.hokudai.ac.jp
or Ken-ichiro Seino: seino@igm.hokudai.ac.jp
Abstract
IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as
a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish,
amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34
belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consen-
sus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized
as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and
receptor-type protein-tyrosine phosphatase-zeta (PTP-𝜁 ) in addition to the chondroitin sulfate
chains of syndecan-1. These interactions result in activating several signaling pathways that reg-
ulate major cellular functions, including proliferation, differentiation, survival, metabolism, and
cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state,
IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-
specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions,
changes in IL-34 expression—increased or decreased—are involved in disease pathogenesis and
correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been
introduced as a newcomer to the big family of interleukins with specific physiological functions,
critical pathological roles, and promising clinical applications in disease diagnosis and treatment.
In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological char-
acteristics, and discussing the importance of IL-34 signaling network in health and disease.

KEYWORDS
CSF-1R ligands, cytokine, development, homeostasis, immunity, inflammation

1 INTRODUCTION cancer, metabolic disorders, and bone diseases.1 Mononuclear phago-

The mononuclear phagocytic system comprises monocyte, M𝝓, den-
dritic cell, Langerhans cell, osteoclast, Kupffer cell, and microglia,
which play crucial physiological roles in development, homeostasis,
tissue remodeling, in addition to immunoregulation of the humoral
and cellular innate and adaptive immunity.1 Dysregulation of this
system is importantly involved in a wide range of pathological
conditions including autoimmunity, inflammation, infection, fibrosis,
Abbreviations: AMPK, AMP-activated protein kinase; CSF-1R, CSF-1 receptor; ECFCs,
endothelial colony forming cells; EIAV, equine infectious anemia virus; FAK, focal adhesion
kinase; HBV, hepatitis B virus; HCV, hepatitis C virus; HO-1, heme oxygenase-1; IAV,
influenza A virus; IDE, insulin degrading enzyme; mHTTx1, amyloidogenic exon-1 fragment of
mutant huntingtin; NAFLD, non-alcoholic fatty liver disease; oA𝛽, oligomeric amyloid 𝛽;
PAMPs, pathogen-associated molecular patterns; PKB/AKT, protein kinase B; PSCs,
pluripotent stem cells; PTP-𝜁, receptor-type protein-tyrosine phosphatase-zeta; RA,
rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-B ligand; SLE,
systemic lupus erythematosus; T2DM, type 2 diabetes mellitus; TAMs, tumor-associated M𝜙s
cytic cells depend largely on signaling mediated by CSF-1 receptor
(CSF-1R)—a type III high-affinity receptor tyrosine kinase expressed
on myeloid progenitors—for their development, survival, prolifera-
tion, and proper functioning.2 Activation of CSF-1R signaling was
thought to be mediated only by the homodimeric growth factor
CSF-1. However, Dai et al. reported an exciting issue that helped to
change the understanding of CSF-1R biology.3 In studies on knock-
out mice, the deficiency of CSF-1R (Csf1r−/− ) resulted in a more
severe osteopetrosis phenotype and a severe systemic depletion of
M𝝓s compared to CSF-1-deficient (Csf1op/op ) mice.3 On the other
hand, CSF-1-deficient mice showed relatively normal numbers of brain
microglia and Langerhans cells of the skin.3 Furthermore, Csf1op/op
mice recover from osteopetrosis with age, suggesting that the lack
of CSF-1 is compensated by an unidentified mechanism. Such dis-
crepancies helped to predict the possible existence of another ligand
for CSF-1R.

Received: 27 February 2018 Revised: 28 May 2018 Accepted: 9 July 2018

J Leukoc Biol. 2018;1–21. www.jleukbio.org 2018
c Society for Leukocyte Biology 1
2 BAGHDADI ET AL .
In a brilliant study that aimed to understand the system of secreted
proteins and receptors involved in cell–cell signaling, Lin et al. iden-
tified a secreted protein with a high functional selectivity repre-
sented by stimulating monocytes survival in a CSF-1R-dependent
manner.4 This protein was encoded by a cDNA clone that differs by
one amino acid residue from a hypothetical protein registered in the
GenBank database (C16orf77, NP_689669), and was designated as
IL-34.4 Later, 2 separate studies by Wang et al. and Greter et al.
described a remarkable decrease in microglia and Langerhans cells
in IL-34-deficient (Il34LacZ/LacZ ) mice, emphasizing the importance of
IL-34 as a tissue-specific ligand for CSF-1R.5,6 When transgenically
expressed in Csf1op/op mice, IL-34 rescued all defects resulted from
CSF-1 deficiency.7 Furthermore, Nakamichi et al. identified pivotal
roles of age-increased IL-34 in the development and maintenance of
osteoclast precursors reservoir in the spleen and their transfer to the
bone in Csf1op/op mice.8 Hence, the discovery of IL-34 was undoubt-
edly the jigsaw piece that completed our understanding of CSF-1R biol-
ogy. Structural studies have then revealed that CSF-1R binds both of
IL-34 and CSF-1, but through distinct surfaces that result in forming
unique receptor conformations and intermolecular interfaces, and cul-
minating in unique downstream signaling events. Described as “ménage
à trois”, this is the only reported case of a hematopoietic receptor
(CSF-1R) that possesses two distinct ligands (CSF-1 and IL-34); a novel
axis that shows high conservation across vertebrates.9
One decade after the discovery of IL-34, research on the physio-
logical and pathological roles of IL-34 has helped to understand the
biology of the mononuclear phagocytic system further, and gave new
insight into the pathogenic mechanisms of several diseases, raising
IL-34 as a potential biomarker and therapeutic target in medicine.10–13
In this review, we celebrate the 10th anniversary of IL-34 discovery
by summarizing the literature focusing on the current knowledge of
IL-34 biology and the importance of IL-34 signaling network in health
and disease.
2 IL-34 BIOLOGY
2.1 Gene and basic structure
Human Il34 gene is located on chromosome 16q22.1 between two
genes: Vac14 and Snord111 loci, and similarly in mouse on chromosome
8E1. At the amino acid level, human IL-34 shares a sequence similarity
of 99.6, 72, and 71% with that of chimpanzee, rat, and mouse orthologs,
respectively.4 IL-34 belongs to the short-chain helical hematopoietic
cytokines, with the smallest dimerization interface among the family
members. IL-34 has no apparent consensus structural domain or motif
and shares no sequence similarity with any other growth factor, includ-
ing CSF-1. The mature full-length of human IL-34 comprises 242 amino
acids. The first 182 amino acids contain predicted N-glycosylation
sites at Asn76 and Asn100 positions, which are vital for IL-34 stabil-
ity and proper folding, in addition to 6 cysteine residues that are highly
conserved among species. Four of these cysteines are critical for the
intramolecular disulfide bonding. The last ∼50 residues at the C ter-
minal are predicted to be largely disordered and highly enriched with
Pro-Ser-Thr amino acids, which is a typical characteristic of flexible
mucin-like O-linked glycosylation-rich sequences.14–19
Ribbon presentations show that IL-34 has a distinctive antiparallel
4-helix core with 2 additional helices integrally bundled to the core, 2
short 𝛽-strands (𝛽1 and 𝛽2) connecting the helices, and unique terminal
extensions used for receptor binding. The 6 𝛼-helices in the bundle are
oriented in an “up–down” fashion with a kink disrupting the first helix
into 2 stretches. The shorter 2 helices (𝛼2 and 𝛼5) are packed against
𝛼3 and 𝛼6 and associated with the 4 longer helices through continu-
ous hydrophobic interactions. The conserved Asn76 glycan serves to
fill the cavity between the 𝛼2 and 𝛼5 helices, explaining its importance
for IL-34 stability. In addition to the interhelical hydrophobic interac-
tions, the helix bundle of IL-34 is further locked by the Cys35-Cys180
disulfide bridge between the first and the last helices (𝛼1 and 𝛼6) at
the fatter end of the bundle, and Cys177-Cys191 disulfide bridge that
locks the C-terminal extension to the end of the 𝛼6 helix (Fig. 1A).14–19
To form a dimer, 2 IL-34 protomers pack against each other with the
thinner ends of their helical bundles, in a head-to-head fashion, forming
a noncovalently linked homodimer.14–19 Additionally, IL-34 was sug-
gested to bind CSF-1 with a low affinity and form a heterodimeric
cytokine able to interact with CSF-1R.20
2.2 Receptors and regulators
Being identified as a highly selective protein that stimulates mono-
cyte viability, Lin et al. searched for an IL-34 receptor in a collec-
tion of extracellular domains of membrane-spanning proteins. Among
10 of 858 extracellular domains that inhibited IL-34 activity in a pri-
mary screen, only 1 protein gave reproducible, specific inhibition in
repeated testing, which was coded by a cDNA of the CSF-1R extracel-
lular domain.4 In functional studies, the activity of IL-34 on monocyte
viability was blocked by specific inhibitors or neutralizing Abs of CSF-
1R, indicating that CSF-1R is a functional receptor for IL-34.4 Later,
studies on the crystal structure of IL-34 have nicely shown that the
noncovalently linked IL-34 homodimer recruits 2 copies of CSF-1R on
the sides of the helical bundles. IL-34 binds to a concave surface formed
by the N-terminal immunoglobulin D2 and D3 domains of CSF-1R,
which is mediated by hydrophobic interactions rather than salt bridge
networks, while D4 domain seems to be involved in IL-34-induced
oligomerization (Fig. 1B).14–19 The hydrophobic/hydrophilic binding
nature of IL-34:CSF-1R and CSF-1:CSF-1R complexes may determine
the differences in functions and signaling activities between IL-34
and CSF-1. In contrast to the CSF-1:CSF-1R complex that depends
on hydrophilic interactions, the IL-34:CSF-1R interface contains a
large number of hydrophobic regions. Given that the disassociation of
hydrophobic contacts is kinetically slower than hydrophilic contacts,
the IL-34:CSF-1R complex is expected to have a longer time span and
thus produce longer and stronger transmembrane signals; an observa-
tion that is supported by in vitro evidence.4
By examining the expression pattern of IL-34 in the brain, Nandi
et al. noticed that IL-34 is expressed in regions where there is a min-
imal expression of CSF-1R or CSF-1, which led to the hypothesis that
IL-34 may signal via an alternative receptor. By utilizing IL-34 affinity
chromatography of solubilized mouse brain membrane followed by
BAGHDADI ET AL . 3

A The discovery of additional receptors for IL-34 encouraged Segaliny

N 35 et al. to search for alternative binding of IL-34 on other cell types. In a
series of binding experiments, IL-34 was found to bind with low affin-
C
191 ity to chondroitin sulfates on cells lacking both CSF-1R and PTP-𝜁 .
177 180 Among these, syndecan-1 modulated the IL-34-induced CSF-1R acti-
vation. More interestingly, IL-34 was able to induce cellular migration
of myeloid cells in a syndecan-1-dependent mechanism. Syndecan-1 is
a type-I transmembrane heparan sulfate proteoglycan involved in cel-
lular proliferation, migration, and matrix interactions. Syndecan-1 also
B acts as a sponge that binds several growth factors via heparan sulfate
CSF-1R
chains. Thus, syndecan-1 may serve as a key regulator of IL-34 biology
D1 IL-34 by controlling IL-34 bioavailability, modulating the recruitment of CSF-
D2 1R chains or the affinity of IL-34 to the receptor chains, and by acting
as a regulator of CSF-1R signaling (Fig. 1C).22
D3
D4 Taken together, IL-34 exerts its biological activities through binding
D5 to CSF-1R in addition to interactions with chondroitin sulfate chains
such as PTP-𝜁 and syndecan-1. In studies on protein structure pre-
diction, Kryshtafovych et al. noticed a highly conserved receptor-free
face within the IL-34 structure, which may serve for a yet undiscov-
ered functional purpose.18 Thus, other molecules may also regulate the

Downstream
signaling
C
Syndecan-1
IL-34
CS
CSF-1R
CSF-1R-downstream CSF-1R-downstream
signaling signaling
Syndecan-1: moderate Syndecan-1: high
FIGURE 1 The basic biology of IL-34. (A) Schematic representa-
tion of the IL-34 structure. IL-34 has a distinctive antiparallel 4-helix
core with 2 additional helices integrally bundle to the core. Two short
𝛽 strands connect the helices. The helix bundle of IL-34 is locked by
disulfide bridges at two sites: C35-C180 and C177-C191. (B) CSF-
1R activation by IL-34. IL-34 homodimer binds to CSF-1R extracellu-
lar domain at the cleft between D2 and D3 resulting in dimerization
and autophosphorylation of tyrosine residues within the intracellular
domain. D4 is involved in IL-34-induced oligomerization. (C) Syndecan-
1 as a regulator of IL-34 biological activities. Levels of syndecan-1
expression are suggested to control IL-34 bioavailability, modulate the
interaction between IL-34 and CSF-1R, and regulate CSF-1R signaling
mass spectrometric analysis, PTP-𝜁 was identified as a novel func-
tional receptor for IL-34. PTP-𝜁 is a cell surface chondroitin sulfate
proteoglycan, primarily expressed on neuronal progenitors and glial
cells. IL-34 binds to the PTP-𝜁 extracellular domain in vitro and on the
cell surface, which was inhibited by chondroitin sulfates, indicating
a dependence of binding on PTP-𝜁 chondroitin sulfate moieties.
Via PTP-𝜁 , IL-34 can stimulate intracellular signaling pathways that
inhibit proliferation, clonogenicity, and motility of the cellular targets,
indicating a CSF1-R-independent action of IL-34.21
biological activities of IL-34, which may be unveiled in future works.
2.3 Signaling networks
IL-34 homodimer binds to CSF-1R extracellular domain at the cleft
between D2 and D3, resulting in autophosphorylation of specific
tyrosine residues within the intracellular domain including Y556,
Y561, Y699, Y708, Y723, Y809, Y873, and Y923. The phosphorylated
residues lead to the recruitment of other kinases and adaptor proteins
that activate several signaling pathways, such as ERK1/2, PKB/AKT,
focal adhesion kinase (FAK), STAT3, and NF-𝜅B (Fig. 2). These signaling
pathways play essential roles in IL-34-mediated survival, prolifer-
ation, differentiation, cytoskeletal organization, cell adhesion and
migration, and cytokine/chemokine expression.11,12 The activation
of these signaling pathways by IL-34 can be observed in a wide range
of CSF-1R-expressing cells, such as myeloid cells, epithelial cells,
endothelial cells, fibroblasts, neurons, and cancer cells. Additionally,
a recent study by Boulakirba et al. suggested that the engagement of
CSF-1R by IL-34 activates caspase and autophagy signaling pathways
through enhanced expression and activation of AMP-activated protein
kinase (AMPK)-1 and UNC-51 like autophagy activating kinase 1 in
monocytes, which were required for IL-34-induced macrophagic
differentiation and polarization.23 On the other hand, activation of
PTP-𝜁 by IL-34 induces tyrosine phosphorylation of FAK and paxillin,
resulting in inhibition of proliferation, clonogenicity, and motility in
specific cellular targets such as glioblastoma cells (Fig. 2).21 IL-34-
induced activation of signaling pathways is importantly modulated by
the interaction between IL-34 and chondroitin sulfate chains at the
cellular surface, notably of syndecan-1. For example, low/moderate
expression of syndecan-1 at the cell surface is associated with the
limited interaction between IL-34 and CSF-1R, while high expression
of syndecan-1 remarkably enhanced IL-34-induced activation of
CSF-1R.22 Thus, the outcome of IL-34-activated signaling pathways
depends on the receptor and regulator in each cellular target.
4 BAGHDADI ET AL .

Pro-inflammatory
cytokines

Chemical PAMPs
stressors
DNA Infection
damaging
agents Vitamin D

IL-34

F I G U R E 2 IL-34 signaling network. IL-34

expression can be induced by several stimuli,
such as DNA damaging agents, chemical stres-
CS
sors, pro-inflammatory cytokines, PAMPs, viral
infection, and vitamin D. The secreted IL-34
Syndecan-1 CSF-1R PTP-
binds to the extracellular domains of CSF-1R
and PTP-𝜁 in addition to the chondroitin sulfate
chains of syndecan-1, resulting in activation
of several signaling pathways that regulate
major cellular functions, including proliferation,
differentiation, survival, metabolism, cytokine/
Ras chemokine expression in addition to cellular
adhesion and migration
Migration PI3K Paxillin FAK
Raf Caspase AMPK1
Src/FAK ULK1

PDK1 STAT3
MEK1/2

Autophagy
AKT
ERK1/2 Proliferation
Motility
c/EBPb Clonogenicity

Cell adhesion, motility, proliferation, survival,

differentiation, polarization, migration,
cytokine/chemokine expression

2.4 IL-34 expression
2.4.1 IL-34 expression in health and disease
During embryogenesis, IL-34 shows early and robust expression in
the neuronal tube before CSF-1, as unveiled by 2 separate stud-
ies on the embryo of mice and chicken.7,24 Using whole-amount
Il34 in situ hybridization, Wei et al. showed that Il34 mRNA was
strongly expressed in the embryonic brain of mice at E11.5 before
Csf1 mRNA, suggesting functional importance of IL-34 during brain
embryogenesis.7 Similarly, Garceau et al. observed a high expression
of Il34 mRNA in the chicken embryo, especially in the neural tube
of the head coincident with the proliferation of CSF-1R-expressing
myeloid populations.24
To identify the cellular resource of IL-34 in adults, Wang
et al. generated transgenic mice in which exons 3–5 of Il34 gene
were replaced by an internal ribosome entry site-lacZ cassette
(Il34LacZ/LacZ ).5 This helped to visualize sites of IL-34 producing
sites by utilizing 𝛽-galactosidase substrate X-gal. At the tissue level,
IL-34 expression was detected in the skin, brain, kidney, and testes. At
the cellular level, IL-34 expression was observed in keratinocytes, hair
follicles, neurons, proximal renal tubule cells, and seminiferous tubule
germ cells. In the brain, IL-34 expression was detected in the cerebral
cortex and hippocampus but not in the cerebellum.5 Nicely replicated
by Greter et al., these observations overlapped the pattern of Il34
mRNA expression in the microarray dataset of the Biology Gene Portal
System (BioGPS).5,6 Thus, while Il34 transcripts can be detected in
various tissues throughout the body, IL-34 can be recognized at the
protein level in a tissue-specific manner; notably in keratinocytes of
the skin and neurons of the brain.5,6
In humans, IL34 mRNA is expressed in various tissues, including
heart, brain, lung, liver, kidney, spleen, thymus, testis, ovary, small
intestine, prostate, and colon, with a remarkable expression in the
BAGHDADI ET AL .
spleen. At the protein level, IL-34 showed strong staining in the
sinusoidal endothelium in the red pulp of the spleen, as unveiled
by immunohistochemistry.4 Similarly, IL-34 shows tissue-enhanced
expression patterns, such as in spleen, brain, and skin according to the
Human Protein Atlas.25
Since IL-34 is expressed at mRNA level in various tissues, this
expression is expected to be changed under pathological condi-
tions. Indeed, several studies have confirmed the enhancement of
IL-34 expression at mRNA and protein levels in the context of vari-
ous diseases including autoimmune disorders,26–47 inflammation,48–63
infections,64–76 metabolic diseases,77–80 neurological disorders,81–93
and cancer.94–106 At the cellular level, IL-34-producing cells include
synovial fibroblasts, immune cells, epithelial cells, endothelial cells,
adipocytes, and cancer cells. On the other hand, a reduction in
IL-34 expression can be observed in certain pathological conditions,
such as in brain tissues in Alzheimer’s disease,91 epidermis in atopic
dermatitis,50 viral infection such as hepatitis B virus (HBV),73 and
periodontal disease.60 In both cases, growing evidence indicates an
essential correlation between changes in IL-34 expression with disease
pathogenesis, progression, and severity.12
In addition to clinical studies, several reports have also evalu-
ated the expression of IL-34 in experimental animal models. IL-34
expression showed an enhancement in murine models of collagen-
or Ab-induced arthritis,39,42 Huntington’s disease,89 dextran sulfate
sodium-induced colitis,52 kidney ischemia,49 systemic lupus erythe-
matosus (SLE) nephritis,43 and sepsis.74 The expression of IL-34 is
also increased in infection models such as in SIV with encephalitis in
rhesus macaques,68 Cryptocaryon irritans in grouper,69 Vibrio anguil-
larum in large yellow croaker,72 and in a fish-parasite infection model
(Enteromyxum leei in Sparus aurata).65
2.4.2 Regulation of IL-34 expression
Although patterns of IL-34 expression have been well identified,
the molecular mechanisms that control this expression remain to be
explored. Due to its highly specific expression patterns, it is of great
interest to examine whether the expression of IL-34 is regulated by
common or different signaling pathways or even by master transcrip-
tion factors in keratinocytes and neurons.
Experimentally, in vitro evidence has shown that IL-34 expres-
sion can be up-regulated by several stimuli relevant to cellular stress
such as stimulation with DNA damaging agents, chemical stres-
sors, pro-inflammatory cytokines, pathogen-associated molecular pat-
terns (PAMPs), in addition to other stimuli such as viral infection
and vitamin D. DNA damaging agents such as cisplatin, doxorubicin,
and pemetrexed activate NF-𝜅B signaling pathway, resulting in up-
regulation of IL-34 expression in cancer cells such as in lung cancer
cells and malignant pleural mesothelioma cells.95,100 Not limited to
cancer cells, etoposide and chemical stressors such as N-methyl-D-
aspartic acid and staurosporine can similarly induce IL-34 expression
in normal neurons.89 Pro-inflammatory cytokines such as TNF-𝛼 and
IL-1𝛽 activates NF-𝜅B and JNK signaling pathways, which increase
the expression of IL-34 in a wide range of cells including fibrob-
lasts, epithelial cells, periodontal ligament cells, osteosarcoma cells,
5
and adipocytes.11,12 Activation of TLRs with PAMPs such as peptido-
glycan, lipopolysaccharide, and nucleic acids mimickers like poly I:C
and CpG induces IL-34 expression in M𝝓s,107 adipocytes,78 and lam-
ina propria mononuclear cells,51 while stimulation with I𝛼,25(OH)2 D3 ;
a hormonally active form of vitamin D, can increase IL-34 expres-
sion in neuroblastoma and normal gastric epithelial cells via vitamin
D receptor.93 The abnormal accumulation of amyloidogenic exon-1
fragment of mutant huntingtin (mHTTx1) modulates the expression of
IL-34 via an NF-𝜅B-dependent mechanism in dopaminergic neurons.89
Finally, hepatitis C virus (HCV)-infected hepatocytes show elevated
levels of IL-34, indicating that IL-34 expression can also be regulated by
infectious pathogens.66 This is supported by the evidence that showed
a direct involvement of equine infectious anemia virus (EIAV)-derived
S2 viral protein in enhancing IL-34 expression in EIAV-infected M𝝓s.64
On the contrast, IL-34 expression can be down-regulated by other
stimuli. For example, stimulation with TGF-𝛽1 and bone morpho-
genetic protein-2 results in decreased expression of IL-34 in TNF-𝛼-
stimulated synovial fibroblasts and mesenchymal stem cells, which is
mediated by activin receptor-like kinase 5 and activin receptor-like
kinase 1, respectively.38 However, TGF𝛽1 can induce IL-34 expres-
sion in hepatocarcinoma cell lines,101 suggesting a cell type-dependent
effect in certain situations.
2.5 IL-34 secretion
IL-34 is synthesized as a secreted homodimeric glycoprotein, consist-
ing of 242 amino acids in human and 235 amino acids in mouse, with
a molecular mass of 39 kD.4 Secreted IL-34 binds to the extracellular
domains of CSF-1R and PTP-𝜁 , in addition to low-affinity interactions
with chondroitin sulfate chains such as in syndecan-1.4,21,22 Several
reports suggested that IL-34 can bind to CSF-1R with higher affinity
than CSF-1 and induce stronger tyrosine phosphorylation of CSF-1R
and downstream molecules.4,100,108 This may be explained by the
characteristics of IL-34:CSF-1R complex that depends on hydrophobic
interactions rather than the salt bridge networks observed in the
case of CSF-1.14–19 The Il34 mRNA in both human and mouse exhibit
alternative splicing of a CAG codon, resulting in isoforms that lack
glutamine residue (Q) at position 81. The absence of Q81 is predicted
to disrupt the second-most amino terminal of 4 𝛼-helices, thus altering
the coiled coil to alpha helix in the nearby structure, which conse-
quently results in reduced biological activities of the secreted IL-34.7
The expression of IL-34 can be detected at mRNA and protein lev-
els in various types of cells. However, the regulation of IL-34 secretion
may depend on cell type. For example, Kawabe et al. have noticed a rel-
atively small number of localization motifs for endoplasmic reticulum
Golgi transport vesicle membrane (YRSR) or the extracellular space
and Golgi apparatus (KALLD) in the sequence of IL-34, indicating that
the affinity to the protein-releasing pathway of IL-34 is weaker than
that for CSF-1 in periodontal ligament cells.109 Consistent with this,
Garceau et al. noticed that the amount of chicken IL-34 overexpressed
in the supernatants of HEK293 cells was considerably less than seen
in cell lysates, which was suspected to be a result of some proteolytic
cleavage by trypsin-like proteases in the medium since many recogni-
tion sites are found at the C-terminal of IL-34.24 Schuster et al. also
6 BAGHDADI ET AL .
found that IL-34 can be measured in the lysates of in vitro generated
epidermal tissues, but not in cell supernatants.110 Furthermore, Lindau
et al. have recently found the IL-34 exists at the protein level at the
human fetal-maternal interface as confirmed by immunohistochem-
istry. However, ELISA measurement showed detectable levels of IL-34
in the lysates of the first-trimester placenta and decidua tissues but
not in the conditioned medium from these tissues. Since IL-34 was co-
expressed with CSF-1, detection of secreted IL-34 could be possibly
impeded by the formed IL-34:CSF-1 heterodimer complex.111 Collec-
tively, the precise molecular mechanisms that control IL-34 secretion
remain to be explored in future studies.
In the extracellular biofluids, IL-34 can be detected at low concen-
trations in serum/plasma, cerebral spinal fluid, synovial fluid, and saliva.
Importantly, accumulating evidence from clinical studies has indicated
a correlation between changes in secreted IL-34 into these extracellu-
lar biofluids with disease parameters in various pathological conditions
such as in rheumatoid arthritis (RA), SLE, heart failure, viral infections,
sepsis, periodontal disease, non-alcoholic fatty liver disease (NAFLD),
obesity, and type 2 diabetes mellitus (T2DM; Table 1). Secreted lev-
els of IL-34 are reduced to normal levels upon successful treatment
of disease, such as in TNF-𝛼-antagonist therapy in RA33 and gastric
bypass surgery in obesity.78 Thus, secreted IL-34 may serve as a poten-
tial biomarker for predicting disease progression and responsiveness
to therapy.
2.6 IL-34 through the evolution journey
IL-34 exists in all types of vertebrates including fish, amphibians, birds,
and mammals.112–119 These species show a similar gene organization
of IL-34, consisting of 7 exons and 6 introns. The phylogenetic tree
analysis showed that IL-34 gene from the primate lineage, rodent lin-
eage, and teleost lineage forms a species-specific cluster. In the major-
ity of genomes, IL-34 gene has 6 exons and 5 introns with similar
lengths in different species. As suggested by Garceau et al., IL-34
is under evolutionary constraint to remain relatively unchanged.112
Consistent with this, site-specific tests for positive selection suggests
that mammalian IL-34 was under positive selection pressure with the
identified positively selected site, 196Val.113
IL-34 shows cross-specificity among species. For example, human
IL-34 activates CSF-1R in human, cat, and pig but not in mouse. On
the other hand, murine IL-34 is capable of activating CSF-1R in mouse,
human, and pig but not in cats. Both human and mouse IL-34 have sim-
ilar activity on the pig and feline CSF-1R.7,114,115 At the amino acid
sequence level, IL-34 is highly conserved among avian and mammalian
species, in contrast to CSF-1.24,112 Consistent with this, a correlated
evolutionary co-variation with CSF-1R can only be detected for IL-34
but not CSF-1. In other words, a change in the genetic composition
of IL-34 would necessarily involve a reciprocal evolutionary change in
CSF-1R. On the other hand, CSF-1 has the flexibility to evolve more
quickly than IL-34 without the need for receptor co-evolving.112 Con-
sidering its specific expression patterns, IL-34 may perform a more
trophic role in the regulation of M𝝓 functions in homeostasis and
development as opposed to innate immunity.
Although IL-34 and CSF-1 can be found in all vertebrates, only IL-34
but not CSF-1 exists in elasmobranches.118 Thus, IL-34 may predate
CSF-1 evolutionary. This could be probably supported by the evidence
that IL-34 mRNA is expressed during embryogenesis before the
expression of CSF-1, and show higher levels in most regions of devel-
oping brain in mice and chicken.7,24 Further investigations into the
distinct roles of IL-34 and CSF-1 in various species will undoubtedly
enrich our understanding of the evolutionary origins and immunologic
mechanisms that control myeloid functional heterogeneity.
3 BIOLOGICAL FUNCTIONS OF IL-34
3.1 Physiological functions of IL-34
The physiological functions of IL-34 have been unveiled by the phe-
notype of knockout mice. In contrast to Csf1r−/− and Csf1op/op mice,
Il34lacZ/LacZ mice show normal lifespan, fertility, bone, blood mono-
cytes, and mostly normal tissue M𝝓s except for Langerhans cells
and microglia that are significantly decreased.5,6 In detail, IL-34 defi-
ciency resulted in decreased frequencies of F4/80+ CD11b+ CD45int
microglia in the brain of neonatal and adult mice. Similarly, the frequen-
cies of F4/80+ CD11b+ CD45+ Langerhans cell precursors in embryo
skin and F4/80+ CD11b+ CD45+ epidermal Langerhans cells in new-
born skin were decreased in IL-34-deficient mice, and CD11b+ CD45+
CD207+ MHC-II+ Langerhans cells in adult skin were almost absent.5,6
Additionally, IL-34-deficient mice show a partial reduction of CD11c+
CD11b+ dendritic cells in the lung compared to wild-type mice.5,6 Con-
sidering its selective expression by keratinocytes and neurons, IL-34 is
expected to specifically direct the differentiation of myeloid cells in the
skin epidermis and brain.
During murine embryogenesis, IL-34 is highly expressed in the epi-
dermis as early as E17.5 and persists after birth. Therefore, IL-34 is
likely to promote the development of Langerhans cells before birth and
maintain their homeostasis throughout life (Fig. 3).5,6,120 However, this
function seems to be restricted to the steady state. Under inflamma-
tory conditions such as in ultraviolet light-induced skin inflammation,
Langerhans cells are dependent on neutrophils-derived CSF-1 rather
than IL-34. Once inflammation is resolved, Langerhans cells recovery
and survival is again IL-34-dependent.58
In the nervous system, IL-34 and CSF-1 exhibit distinct devel-
opmental brain expression patterns and regulate neuronal progeni-
tor cell maintenance and maturation.121 In contrast to Langerhans
cells, microglia and their yolk sac precursors develop independently of
IL-34 during embryogenesis but rely on it for their maintenance in spe-
cific regions of the adult brain (Fig. 3). During embryonic development
in chicken, IL34 mRNA is highly expressed in the embryo, especially in
the neural tube of the head at the time of proliferation of the M𝝓 pop-
ulations expressing CSF1R mRNA.24 In mouse, the expression of IL-34
and CSF-1 can be detected in the developing brain as early as E12.5,
but this expression occurs in complementary regions of the cortex. At
day E15.5, IL-34 expression is restricted to the cortical marginal zone
while CSF-1 is detected within the subventricular zone and the ven-
tricular zone. In the neonatal cortex, the CSF-1 expression is restricted
BAGHDADI ET AL .
TA B L E 1 in disease
Disease
Alzheimer’s disease
Ankylosing spondylitis
Atopic dermatitis
Cancer
Chronic apical periodontitis
Chronic heart failure
Coronary artery disease
Diabetic nephropathy
Hepatitis B viral infection
Hepatitis C viral infection
Inflammatory bowel disease (Crohn’s
disease, ulcerative colitis)
Influenza A viral infection
Liver transplantation
Microvesicular steatosis
Non-alcoholic fatty liver disease
Obesity
Periodontal disease
Psoriasis and psoriatic arthritis
Rheumatoid arthritis
Sepsis
Sjogren’s syndrome
7
Clinical observations Reference
91
IL-34 is decreased in the inferior temporal gyrus in some patients with Alzheimer’s
disease
32
Elevated levels of serum IL-34
IL-34 is decreased in lesional compared to non-lesional atopic dermatitis and normal 50
epidermis
Breast cancer: high expression of Il34 mRNA in brain metastasis 97
Cholangiocarcinoma: elevated levels of serum IL-34 104
94
Giant cell tumors: IL-34 is strongly expressed in osteoclast cells, and inversely related
with CSF-1.
101
Hepatocellular Carcinoma: high expression of IL-34 correlates with poor prognosis and
recurrence
95
Malignant Pleural Mesothelioma: IL-34 is secreted by malignant pleural mesothelioma
cells and drives chemoresistance
106
Melanoma: high expression of IL-34 correlates with frequencies of CD163+ cells in
Nivolumab-resistant metastatic melanoma
100,105
Lung cancer: high expression of IL-34 correlates with tumor progression and poor
survival
97
Lung cancer: high expression of Il34 mRNA in brain metastasis
98
Osteosarcoma: heterogenous expression of IL-34 in human osteosarcomas
Sporadic colorectal cancer: overexpression of IL-34 in cancer tissues 102
High expression of IL-34 in lymphocytes, plasma cells, and macrophages within chronic 54
periapical lesions
High levels of serum IL-34 correlates with increased risks of renal dysfunction, 53,61
cardiovascular death, hospitalization, and mortality
High levels of serum IL-34 correlates with high-sensitivity C-reactive protein 48
79
IL-34 correlates with increased risk of diabetic nephropathy in Han Chinese patients
with type 2 diabetes
73
IL-34 is reduced in the serum and PBMCs of chronic HBV patients, and negatively
corelates with disease activity parameters 76
Serum IL-34 is increased in HBV infection and correlates with liver inflammation and
fibrosis in chronic HBV patients
66
High levels of serum IL-34 correlates with advances stage of liver fibrosis
IL-34 expression is significantly increased in the epithelial layer and connective 51,52
tissues-infiltrating immune cells within the inflamed mucosa
High levels of IL-34 in serum and PBMCs 71
56
High levels of serum IL-34 during acute rejection
66
Enhanced expression of IL-34 in hepatocytes
57,66
High levels of serum IL-34 correlates with disease stage
Elevated serum IL-34 in obese women associates with metabolic parameters, reduced 78
after gastric bypass surgery
IL-34 is decreased in saliva of patients with periodontitis 60
62
High levels of IL-34 in gingival crevicular fluid and plasma of patients with chronic
periodontitis, further increased when accompanied with T2DM
47
High levels of serum IL-34 correlates positively with circulating osteoclast precursors
27,30–32,34,40
High levels of IL-34 in serum correlates with disease activity
26,27,30–32,36,38
High levels of IL-34 in synovial fluid correlates with disease activity
High expression of IL-34 in the synovial lining layer (synoviocytes, multinucleated giant 26,32,35
cells, and macrophages) and the sibling layer (endothelial cells, inflammatory cells, and
fibroblasts) correlates with total leucocyte counts and synovitis severity
33
Serum IL-34 predicts good response of TNF𝛼 antagonist therapy at 3-months treatment
High levels of IL-34 in the serum 74
46
IL-34 is overexpressed in ductal epithelial cells and infiltrating mononuclear cells of the
inflamed salivary gland, and correlates with pro-inflammatory cytokines (TNF𝛼, IL-1𝛽)
and local expansion of pro-inflammatory CD14bright CD16+ monocytes
(Continues)
8 BAGHDADI ET AL .

TA B L E 1 (Continued)

Disease Clinical observations Reference

Systemic Lupus Erythematosus High levels of serum IL-34 correlates positively with SLE disease activity parameters 44,45

Type II diabetes mellitus IL34 is located within characteristic risk loci of T2DM 77

80
Serum IL-34 serves as a potential inflammatory factor for predicting the risk of vascular
diabetic complications

Central nervous system

Neurons

IL-34

CSF-1R

F I G U R E 3 Physiological functions of IL-34. IL-

Microglia
34 is constitutively expressed by neurons and ker-
atinocytes, and play critical roles in the development
and maintenance of microglia and Langerhans cells in
Skin epidermis Keratinocytes the brain and skin, respectively

IL-34
CSF-1R

Langerhans cells

to neurons in layer VI, while IL-34 expression extends from neurons
at layer V to layer II. IL-34 is expressed in regions of the brain other
than the cortex, including the hippocampus and striatum. Expression of
IL-34 is comparatively lower in white matter and is essentially absent
from the cerebellum and brain stem. In addition to neurons, IL-34 is
present in ependymal cells lining the ventricular system and in the
choroid plexus, suggesting that IL-34 can be secreted into the cere-
brospinal fluid. Consistent with the selective production of IL-34 in cer-
tain areas of the brain, Il34LacZ/LacZ mice show severely reduced num-
bers of microglia in corresponding regions of the brain, particularly the
cortex and hippocampus.5–7
Collectively, IL-34 serves as a tissue-restricted ligand of CSF-1R
required for the development and maintenance of Langerhans cells
and microglia (Fig. 3). Adult Langerhans cells require IL-34 to contin-
ually self-renew in the steady state. Similarly, microglia relies on
IL-34 for survival and homeostasis is specific regions of the
brain.120,121 Despite their normal phenotype at the steady state,
Il34-deficient mice responded poorly to skin antigens and viral
infections of the central nervous system, indicating the physiological
importance of IL-34.5,6
In addition to keratinocytes and neurons, IL-34 can be detected at
the protein level in proximal renal tubule cells, seminiferous tubule
germ cells, and spleen.4–6 In a recent study by Tribulo et al., IL-34
was identified as one of the candidate molecules used by the mater-
nal reproductive tract to regulate development of the preimplantation
embryo in bovine. IL-34 with other 10 genes were highly expressed
at the estrus and affected by day of the estrous cycle.122 Further-
more, Lindau et al. have recently identified a possible involvement
for IL-34 expressed by placental cyto- and syncytiotrophoblasts and
decidual stromal cells at the human fetal–maternal interface in estab-
lishing the tolerant milieu by altering M𝝓 polarization into a regula-
tory phenotype.111 Collectively, the physiological importance of IL-34
expression in these conditions remains to be explored in future works.
3.2 The impact of IL-34 on cellular functions
On the contrast of its tissue-specific expression and particular func-
tions in vivo, IL-34 shows similar biological activities with CSF-1 in
vitro, controlling the biology and function of mononuclear phagocytic
cells. Consistent with this, when transgenically expressed in mice in
a spatiotemporal manner mimicking CSF-1, mouse IL-34 was able to
rescue all defects in the bone, osteoclast, tissue M𝝓s, and fertility
observed in Csf-1op/op mice, indicating a functional overlap between
BAGHDADI ET AL . 9

IL-34 and CSF-1.7 However, several studies have also unveiled the abil- monocyte-like cells, characterized by alterations in specific cell mark-
ity of IL-34 to exhibit particular functions that differ from CSF-1 in cer- ers and functional ability to phagocytize foreign particles and perform
tain conditions, which will be together introduced here. respiratory burst activity.96

3.2.1 Cell proliferation and survival 3.2.3 Cell adhesion and migration
A novel role for IL-34 in cell adhesion and migration has been
IL-34 binds CSF-1R and induces activation of ERK1/2 and AKT signal-
described in several studies. The observation that IL-34 expression is
ing pathways required for the proliferation and survival of cells of the
accompanied with angiogenesis and M𝝓 recruitment in osteosar-
myeloid lineage including bone marrow cells, monocytes, M𝝓s, osteo-
coma has led Segaliny et al. to investigate whether IL-34 has a direct
clasts, and microglia.11,12 Similar biological effects can be observed
effect on monocyte adhesion to the endothelium. As expected, IL-34
in other cell types including endothelial cells, fibrocytes, and cancer
preconditioning was found to promote in vitro adhesion of CD14+
cells. IL-34 promotes proliferation of endothelial colony forming cells
monocytes or CD34+ hematopoietic stem cells into endothelial cell
(ECFC), which is dependent on the glycosaminoglycans at the cell
precursors and mature HUVEC monolayers.98 Similarly, IL-34 was also
surface.98 Furthermore, IL-34 induces STAT3 activation and miRNA-
found to promote the adhesion of osteoclast progenitors and M𝝓s in
21 increment in synovial fibroblast, resulting in increased resistance
vitro culture.27,108
of fibroblast to apoptosis in RA.36 In an autocrine manner, IL-34 pro-
Upon the identification of syndecan-1 as a regulator of IL-34 bio-
vides a critical survival signal to CSF-1R-expressing cancer cells by
logical activities, Segaliny et al. tried to elucidate the functional impli-
enhancing activation of ERK1/2 and AKT signaling pathways and thus
cation of the syndecan-1/IL-34 interactions. Interestingly, IL-34 was
contributes to chemoresistance such as in lung and colon cancer cells
found to induce a significant increase in the migration of syndecan-1-
in addition to malignant pleural mesothelioma cells.95,100,102 On the
expressing THP-1 monocyte cell line and M2a-polarized M𝝓s. A block-
other hand, IL-34 can inhibit the proliferation in other cells such as
ing anti-syndecan-1 Ab could inhibit the IL-34-induced THP-1 and
glioblastoma cells via a PTP-𝜁 -dependent mechanism.21
M2a M𝝓 migration, indicating that IL-34 can induce the migration of
myeloid cells in a syndecan-1-dependent mechanism.22
3.2.2 Cell differentiation
IL-34 can substitute for CSF-1 entirely for inducing the differentiation
3.2.4 Angiogenesis
of monocytes into M2-polarized M𝝓s that exhibit enhanced immuno-
The role of IL-34 in angiogenesis has been confirmed by Segaliny
suppressive properties.123,124 The activation of ERK1/2, AKT, AMPK,
et al. in a murine preclinical model of osteosarcoma. In this model,
and autophagy signaling pathways are required for IL-34-induced
the overexpression of IL-34 in osteosarcoma cells was associated
M𝝓 differentiation and polarization.23 In Kupffer cells, IL-34 alters
with enhanced tumor growth and lung metastases of osteosarcoma,
Kupffer cells polarization into an M2-phenotype, characterized by
in addition to an increase in neo-angiogenesis. Histological inves-
decreased expression of pro-inflammatory cytokines such as IL-12, and
tigations unveiled that the density of neo-vessels was significantly
increased expression of immunosuppressive cytokines, including Arg-
increased in tumors overexpressing IL-34 compared to the control
1, IL-10, and TGF-𝛽1. The responsible mechanism was mediated by the
group. The pro-angiogenic potential of IL-34 was further confirmed
IL-34-induced activation of the PI3K/Akt pathway, enhancement of the
experimentally in vitro, where IL-34 was able to recruit endothe-
phosphorylation of mTOR, S6K, and 4E-BP, and suppression of p65 and
lial cells to form vascular structures. In two endothelial cell lines,
p38 MAPK activation.125
ECFCs and HUVECs, IL-34 activates several kinases including PI3K,
Similar with CSF-1, the combination between IL-34 and receptor
Src, FAK, and ERK1/2, which importantly contribute to cell differ-
activator of NF-𝜅B ligand (RANKL) orchestrates osteoclast differen-
entiation into vascular cords. These effects were mediated by the
tiation and survival. IL-34 activates signaling pathways downstream
interaction between IL-34 and glycosaminoglycans at the cellular
of CSF-1R, which modulate cell adhesion, differentiation, fusion, and
surface, indicating a CSF-1R-independent mechanism.98 Addition-
resorbing activity in osteoclast precursors, while RANKL is dedicated
ally, IL-34 can exert additional pro-angiogenic functions via CSF-1R-
to osteoclast fusion, activation, and survival.94,126 However, IL-34
dependent mechanisms, by inducing the secretion of several factors
shows selective biological effects on the differentiation of specific cell
that contribute to angiogenesis such as IP-10, MCP-1, and IL-8 in
types. For example, when combined with GM-CSF, IL-34 but not CSF-1
PBMCs.132 Added to its effects on the mononuclear phagocytes adhe-
can induce monocytes differentiation into microglia-like cells, referred
sion to the endothelium,98 IL-34 is expected to play essential roles
to as induced microglia, which serves as a novel translational research
in angiogenesis.
tool for analyzing the underlying microglial pathophysiology in psychi-
atric disorders, such as Nasu-Hakola disease.127,128 On the other hand,
a mixture of IL-34, CSF-1, GM-CSF, and TGF-𝛽1 can induce microglial 3.2.5 Metabolism
differentiation from pluripotent stem cells (PSCs).129,130 More inter- In a cohort of female Koreans, Chang et al. described a potential role
estingly, IL-34 can selectively induce the differentiation of splenocytes for IL-34 in metabolism. Serum IL-34 levels were elevated in obese
into follicular DC-induced monocytic cells that show B cell-stimulating women and associated with several metabolic parameters. IL-34
activity.131 Finally, an interesting study by Booker et al. has described expression was detectable in adipose tissues, and this expression
the ability of IL-34 to induce differentiation of leukemia cell lines into increased during adipogenesis or inflammation under the effects
10
of pro-inflammatory cytokines such as TNF-𝛼 and IL-1𝛽. Thus,
adipocytes-derived IL-34 may contribute to M𝝓 recruitment into
adipose tissues, which is one of the central features of obesity-induced
inflammation. Additionally, IL-34 can exert direct biological effects
on adipocytes. For example, treatment of adipocytes with high con-
centrations of IL-34 significantly inhibited the stimulatory effects of
insulin on the uptake of 2-deoxyglucose. Furthermore, the presence of
IL-34 during adipogenesis increases the accumulation of triglycerides
in pre-adipocytes. From these observations, IL-34 was expected to be
involved in insulin resistance in obesity.78
In addition to adipocytes, Boulakirba et al. noticed a robust
activation of the AMPK metabolic signaling pathway in IL-34-
differentiated M𝝓s, which importantly contribute to their M2-
polarized phenotype.23 Furthermore, several genes related to lipid
metabolism, transport processes, in addition to enzymatic regulators
of cholesterol and triglyceride pathways are remarkably activated dur-
ing IL-34-induced M𝝓 differentiation.124
3.2.6 Neuroprotection
The central nervous system is one of the few places that show constitu-
tive expression of IL-34 in the steady state. Growing evidence from in
vitro experiments, animal models, and clinical studies suggests a neuro-
protective role of IL-34 in brain injury and neurodegeneration. IL-34 is
constitutively expressed by neurons, and this expression is significantly
increased in damaged neurons. IL-34 is released from injured neurons
and acts as a “Help-me” signal that induces potent neuroprotective
functions by exerting critical biological effects on neurons, microglia,
and endothelial cells of the blood–brain barrier.92 As suggested by Luo
et al., CSF-1R is expressed in neurons and up-regulated after brain
injury. IL-34 protects neurons against excitotoxic-induced neurode-
generation by maintaining CREB signaling downstream of CSF-1R in an
autocrine manner. Consistent with this, in vivo administration of IL-34
protected mice from excitotoxin-induced neuronal loss and gliosis.84
In microglia, IL-34 enhances microglial neuroprotective functions by
inducing the expression of 2 enzymes, insulin degrading enzyme (IDE)
and heme oxygenase-1 (HO-1). IDE is an enzyme required for the
degradation and clearance of oligomeric amyloid 𝛽 (oA𝛽), while HO-
1 is an antioxidant enzyme that suppresses reactive oxygen products
induced by oA𝛽.81 Additionally, IL-34 induces microglial production of
TGF-𝛽1, which in turns negatively regulates microglial proliferation but
attenuated oA𝛽-mediated neurotoxicity.82 Finally, IL-34 is suggested
to have a novel role in restoring the integrity of blood–brain barrier
within the brain. Tight junction proteins of the capillary endothelial
cells play essential roles in the barrier function of the blood–brain bar-
rier and are frequently downregulated by pro-inflammatory cytokines
such as TNF-𝛼 and IL-1𝛽. In an interesting study by Jin et al., IL-34
was able to antagonize the effects of TNF-𝛼 and IL-1𝛽 on endothelial
cells, resulting in the up-regulation of tight junction proteins including
claudin-5 and occludin via a CSF-1R-mediated mechanism.85
3.2.7 Immune response
Inflammation is a vital biological process that enables the host to
develop a protective response to injury, pathogen, cancer, or immune
BAGHDADI ET AL .
deregulation. Through a complex signaling network that involves
various types of cells and molecules, IL-34 play important roles in
orchestrating innate and adaptive immune responses during inflam-
mation, which has been well established by in vitro experiments and
animal models. The expression of IL-34 can be induced by various
stimuli relevant to inflammation such as pro-inflammatory cytokines,
PAMPs, infections, chemical stressors, and tissue injuries.11,12 Several
studies have shown that IL-34 expression is regulated by NF-𝜅B,
which is a central molecule that governs all signaling pathways
related to inflammation.133,134 Upon secretion into the inflamma-
tory loci, IL-34 is expected to play multiple roles that seem to be
highly dependent on the cellular and molecular components of the
local microenvironment.
IL-34 has the potential to amplify the inflammatory circle by induc-
ing the expression of several pro-inflammatory cytokines, chemokines,
and metalloproteases in a wide range of cells including monocytes,
M𝝓s, microglia, fibroblasts, and epithelial cells.11,12 The existence of
IL-34 is accompanied by the expansion of pro-inflammatory mono-
cytes in the inflamed loci, such as in the inflamed salivary glands.46,63
Additionally, Foucher et al. have identified an important characteristic
of IL-34-differentiated M𝝓s, represented by the constitutive expres-
sion of the membrane IL-1𝛼. Membrane IL-1𝛼 is involved in rendering
noncommitted memory T cells into a conventional Th17-cell pheno-
type. Thus, this mechanism allows M𝝓s to maintain locally restrained
and smoldering inflammation by favoring the switch of memory CD4+
T into Th17 cells.135 Boulakirba et al. showed a similar function of
IL-34-differentiated M𝝓s in the regulation of T cell response, which
was importantly affected by stimuli available at the local microen-
vironment. In detail, the expression of cytokines/chemokines differs
in IL-34-differentiated M𝝓s depending on their polarization status,
which importantly impacts their ability to polarize naïve T lympho-
cytes into Th1 cells. For example, IL-10 production is increased in
IL-34-differentiated M𝝓s polarized into M1-phenotype by LPS and
IFN-𝛾 stimulation, resulting in a decrease in Th1 cell polarization. On
the contrast, IL-4 induces a shift in IL-34-differentiated M𝝓s into an
M2-polarized phenotype that showed enhanced expression of CCL17
and CCL22, thus favored an increase in Th1 polarization.23
On the other hand, IL-34 can also act as an immunosuppressive
cytokine that contributes to inflammation resolution and immune
tolerance. IL-34 induces monocytes differentiation into M2-polarized
M𝝓s characterized by enhanced immunosuppressive capacities to
inhibit NK and T cell responses.66,100,123 Additionally, IL-34 medi-
ates an anti-inflammatory shift in cytokine/chemokine production
in stimulated M𝝓s, and down-regulation of TLRs such as TLR2
and Dectin-1.23,70 Furthermore, Bézie et al. demonstrated a novel
connection between IL-34-differentiated M𝝓s and Tregs that medi-
ates immune tolerance. In the presence of IL-34, M𝝓s significantly
expanded CD8+ and CD4+ FoxP3+ Tregs with a superior suppressive
potential to control immune responses and induce immune tolerance,
such as in a rat cardiac allograft model and graft vs. host disease
in humanized mice.136–138 Collectively, IL-34 may have important
roles in orchestrating the innate and adaptive immune responses via
regulating cytokine/chemokine expression and rendering M𝝓s into
distinct phenotypes.
BAGHDADI ET AL .
4 PATHOLOGICAL ROLES OF IL-34
Despite its selective expression in the skin and brain in the steady
state, accumulating evidence has unveiled important roles of IL-34
in various pathological conditions.12 In each disease, IL-34 can tell
different stories depending on the cellular origin, the molecular and
cellular components in the surrounding microenvironment, in addition
to the availability and expression magnitude of receptors and regu-
lators related to IL-34 such as CSF-1R, PTP-𝜁 , and syndecan-1. The
expression of IL-34 is accompanied by disease severity and progression
in some cases, but can also show beneficial effects in others. Accord-
ingly, the role of IL-34 in disease is complex, controversial, and highly
context-dependent. Here, we summarize the major pathological roles
of IL-34 described in the literature.
4.1 Autoimmune diseases
The pathological roles of IL-34 in autoimmune disorders have been
evaluated in several diseases such as RA, Sjogren syndrome, SLE, psori-
asis, and psoriatic arthritis. RA is a chronic autoimmune disease of the
joints characterized by synovial inflammation and hyperplasia result-
ing in progressive cartilage and bone destruction. Pro-inflammatory
cytokines are fundamental to the pathophysiology of RA. Numer-
ous studies have unveiled the pathologic role of IL-34 in RA as a
downstream effector of pro-inflammatory cytokines, contributing
importantly to inflammation and bone erosion.26–42 Elevated levels of
IL-34 can be detected in the blood, synovial fluids, and synovial tissues
of RA patients. At the cellular level, IL-34 expression can be detected
in a wide range of cells, including synoviocytes, multinucleated giant
cells, and M𝝓s in the synovial lining layer, and endothelial cells,
inflammatory cells, and fibroblasts in the sublinig layer of synovial
tissues.26 Evidence from in vitro experiments has shown that pro-
inflammatory cytokines, including TNF-𝛼, IL-1𝛽, IL-6, and IL-17, can
induce the expression of IL-34 in osteoblasts and synovial fibroblasts
via JNK- and NF-𝜅B-mediated mechanisms.26,28,133 Functionally,
IL-34 contributes to the pathophysiology of RA via multiple molecular
and cellular mechanisms: (1) IL-34 mediates a positive feedback loop
that results in an enhanced expression of pro-inflammatory cytokines
such as IL-6 and IL-17,36,40–42 (2) promotes migration of PBMCs that
showed enhanced expression of IL-17,41 (3) enhances proliferation
and differentiation of M𝝓s, which serve as a predominant infiltrating
cell type in the inflamed synovia that promotes inflammation by
enriching the environment with pro-inflammatory factors,26 and
(4) supports RANKL-induced osteoclastogenesis resulting in bone
erosions.27 Additionally, IL-34 induces STAT3 activation and miRNA-
21 increment in synovial fibroblast, resulting in increased resistance
of fibroblast to apoptosis and enhanced IL-6 expression, which in turns
contribute to Th17 production.36 A recent study by Galligan et al. have
suggested a novel role of IL-34 in simulating fibrocyte proliferation
and activating during arthritis, thereby contributing to both onset
and systemic spread of the disease in a murine model of collagen-
induced arthritis (Fig. 4A).39 Using the same model, IL-34 was found
to aggravate disease severity by enhancing levels of pro-inflammatory
cytokines such as IL-6, IL-17, and TNF-𝛼.39,42
11
Sjogren’s syndrome is a chronic inflammatory autoimmune disease
characterized by the disturbance of cytokine networks and the pres-
ence of focal B and T cell infiltration. The pathogenesis of Sjogren’s
syndrome is considered to be multifactorial, and epithelial cells of
the salivary glands are suggested to play important pathological roles
represented by the massive secretion of several pro-inflammatory
cytokines in the histopathological lesions. In clinical samples from
patients with Sjogren’s syndrome, Cicca et al. observed an increased
expression of IL-34 in infiltrating mononuclear cells and ductal epithe-
lial cells in the inflamed salivary glands. The increased expression of
IL-34 was found to be associated with increased expression of pro-
inflammatory cytokines, such as TNF-𝛼, IL-1𝛽, IL-17, and IL-23p19.
Importantly, IL-34 expression was accompanied by the expansion of
pro-inflammatory CD14Bright CD16+ monocytes in the inflamed sali-
vary glands; an observation supported experimentally by in vitro
evidence. Thus, IL-34 is suggested to involved in the pathogenesis of
salivary gland inflammation in Sjogren’s syndrome.46
SLE is a heterogeneous multisystemic autoimmune inflammatory
disease characterized by polyclonal activation of T and B lymphocytes,
production of auto-antibodies, and formation of immune complexes
that result in tissue and organ damage. Two separate studies by Wang
et al. and Xie et al. have found elevated levels of serum IL-34 in SLE
patients and correlates with the accumulation of the related clinical
features.44,45 The role of IL-34 in SLE is supported by evidence from
experimental animal models. In comparative transcriptional profiling
of 3 murine models of SLE nephritis has revealed unique and shared
regulatory networks, and IL-34 was one of the factors shared between
these 3 models, showing enhanced expression in the SLE kidney
nephritis.43 The pathological function of IL-34 SLE in addition to other
autoimmune disorders remains to be explored in future works.
4.2 Inflammation
The involvement of IL-34 in inflammation has been suggested by the
evidence that showed induced expression of IL-34 in a wide range
of cells upon exposure to various inflammatory stimuli that activate
NF-𝜅B such as pro-inflammatory cytokines, PAMPs, and chemical
stressors.11,12 Specific inhibitors of NF-𝜅B can sufficiently reduce
IL-34 expression after stimulation, indicating that NF-𝜅B regulates
IL-34 expression in stimulated cells.133,134 Since NF-𝜅B is a master
regulator of the inflammatory signaling pathway, IL-34 is expected to
be correlated with various inflammatory conditions. Consistent with
this, an enhanced expression of IL-34 has been reported in several
pathological conditions accompanied by inflammation such as inflam-
matory bowel disease,51,52 coronary artery disease,48,53,61 chronic
apical periodontitis,60 obesity,78 chronic liver disease in NAFLD,57 and
lesions of the salivary glands.46,63 Importantly, IL-34 was suggested
to be involved in the pathological complications of these chronic
conditions, such as renal dysfunction in chronic heart failure,61 liver
fibrosis in NAFLD,57 and insulin resistance and T2DM in obesity.78,80
In 2 separate studies by Zwicker et al. and Franzè et al., IL-34 was
identified as a novel modulator of human and experimental inflam-
matory bowel disease, which importantly sustains inflammatory path-
ways in the gut. IL-34 expression was increased at both mRNA and
12 BAGHDADI ET AL .

IL-1β
A IL-6
Synovial
B
PAMPs TNFα
TNFα IL-17 Fibroblast
Osteoblast Colon epithelium

IL-34
NF-Kβ↑

Synovial PBMCs
Fibroblast IL-34
Fibrocyte PBMCs Macrophage

Proliferation
STAT3 Activation Colon
Migration Cytokines/chemokines
miR-21 Increment epithelium
IL-17
Proliferation ERK1/2
Proliferation IL-1β
IL-6
IL-8
Survival MCP1
IL-17 cells↑ CCL2 IL-6 TNFα
Onset

Damage
CSF-1R
C D
Neuron • Survival
• Tumor growth
• Metastasis Cancer cell
IL-34 • Stemness
• Therapeutic
resistance IL-34

IL-34 IL-34
IL-34
CSF-1R
CSF-1R CSF-1R
Endothelial
Neuron Microglia
cells
Claudin-5, Occludin Osteoclasts
CREB BBB integrity IDE, HO-1 Monocytes Endothelial cells
Survival Chronic
TGFβ recruitment
Activation
• Survival
• Tumor growth Angiogenesis
Neuroprotection • Metastasis Bone destruction
Pro-inflammation • Stemness
cytokines • Therapeutic
Neuroinflammation Necrotic factors resistance

F I G U R E 4 Pathological roles of IL-34. The role of IL-34 in disease is complex, controversial, and highly context-dependent. Via complex networks
that involve different cells and molecules, IL-34 exhibits various pathological roles such as in RA (A), inflammatory bowel disease (B), neurological
disorders (C), and cancer (D). In most cases, enhanced expression of IL-34 is accompanied by disease severity and progression

protein levels in the inflamed colon of patients with Crohn’s disease
and ulcerative colitis. Stimulation with the pro-inflammatory cytokine
TNF-𝛼 significantly induced the expression of IL-34 in colon epithe-
lial cells via an NF-𝜅B-mediated mechanism. On the other hand, stim-
ulation of colon epithelial cells with IL-34 enhances the expression
of pro-inflammatory cytokines and chemokines such as TNF-𝛼, IL-6,
and CCL20 through an ERK-dependent mechanism. Thus, IL-34 is sug-
gested to mediate a positive feedback loop that results in the amplifica-
tion of the inflammatory circuit by enriching the inflammation loci with
pro-inflammatory cytokines and enhancing the infiltration of inflam-
matory lymphocytes (Fig. 4B).51,52,140 A recent study by Zwicker et al.
has described the expression of IL-34 receptors in the gut. CSF-1R
and PTP-𝜁 were detectable at the protein level in both immune cells
and intestinal epithelial cells. The expression of PTP-𝜁 was high in the
colon but weak in PBMCs and monocytes/M𝝓s. CSF-1R showed high
expression in monocytes/M𝝓s but was also detectable in intestinal
epithelial cells. Importantly, PBMCs and monocytes responded differ-
entially to IL-34 and CSF-1 stimulation with altered expression of pro-
inflammatory cytokines and chemokines. Taken together, the patholog-
ical roles of IL-34 during inflammation is suggested to be importantly
impacted by the cellular expression patterns of the related recep-
tors, CSF-1R and PTP-𝜁 .139 Recently, a brilliant study by Jodeleit et al.
that validates the disease network in the NOD-SCID
ulcerative colitis animal model, have suggested a new method based
on combining between mRNA expression analysis and effects of
cytokines, chemokines, and growth factors described in the literature
to get a better understanding of the inflammatory processes in disease.
In this model, IL-34 was suggested to induce Th2-drive inflammation,
which may result in activation of the inflammatory remodeling condi-
tion. This inflammatory condition might be responsible for fibrosis and
epithelial hyperplasia in patients with ulcerative colitis.59
In addition to inflammatory bowel disease, a crucial pathologic role
of IL-34 has been described in kidney inflammation. During kidney
injuries, M𝝓s play critical roles in the regulation of inflammatory
response to injury, which can be beneficial leading to kidney repair,
or harmful resulting in kidney destruction. While tubular cell-derived
CSF-1 is required for kidney repair, Baek et al. have identified tubular
cell-derived IL-34 as a critical inflammatory mediator that contributes
to kidney injury. Studies on Il34LacZ/LacZ mice showed that IL-34
expression could be detected in renal tubule cells.5,6 In a murine model
of ischemia-reperfusion kidney injury, IL-34 expression raised rapidly
in tubular epithelial cells during the acute phase and promoted tubule
destruction by infiltrating M𝝓s and neutrophils in the inflamed kidney.
Upon chronicity, IL-34 worsens chronic kidney disease by 2 distinct
mechanisms: (1) enhanced intrarenal M𝝓 infiltration and (2) elevated
IL2r𝛾 null NSG proliferation of bone marrow-derived myeloid cells, which increases
BAGHDADI ET AL .
circulating monocytes and neutrophils that are recruited by several
chemokines induced by IL-34 in the injured kidney. Thus, IL-34 was
suggested to promote persistent ischemia-incited acute kidney injury
and worsens the subsequent chronic kidney disease.49,55
4.3 Infections
Dysregulation of cytokines and chemokines expression occurs during
viral infections and importantly contribute to modulating viral repli-
cation, persistence, and disease progression. The second appearance
of IL-34 in the literature was in an interesting study by Covaleda et al.
that described for the first time a pathological potential of IL-34 in
viral infections. In a model of EIAV infection, monocyte-derived M𝝓s
showed enhanced expression of IL-34 upon EIAV infection, which
was selectively dependent on the existence of the viral protein, S2.
Macrophages are the natural target for EIAV replication. In addition
to their roles as viral reservoirs, infected M𝝓s serve as vehicles that
enable the virus to reach different tissues and organs. Considering the
biological importance of IL-34 in promoting the formation and prolif-
eration of monocyte/M𝝓 lineage in the bone marrow, EIAV-induced
IL-34 may help to promote a suitable cellular environment that is likely
to enhance viral replication and dissemination.64 HIV, a retrovirus
closely related to EIAV, depends on M𝝓s at the early phase for estab-
lishing the HIV infection. Similarly, M𝝓s enhance HIV production and
dissemination to other cells and tissues and aid viral persistence by
serving as a long-lived cellular reservoir of HIV in several tissues. Chi-
hara et al. provided evidence of the potential involvement of IL-34 in
HIV infection by showing that HIV-1 replication is tended to be higher
in IL-34-differentiated M𝝓s due to the strong activation of MAPK
signaling pathway downstream of CSF-1R.108 Therefore, it is reason-
able to suspect that IL-34 supports the development and maintenance
of HIV-M𝝓 reservoirs through CSF-1R signaling. Later, Gerngross
et al. showed robust IL-34 expression in brain parenchyma of SIV-
infected rhesus macaques. Importantly, in vitro stimulation with IL-34
enhanced HIV-1 production in microglia and expanded IL-10+ mono-
cytes via a CSF-1R-mediated mechanism. Thus, IL-34 may contribute
to HIV-associated neuropathogenesis by maintaining alternative M𝝓
polarization and providing critical pro-survival signaling that protects
infected M𝝓/microglia from apoptosis.67,68,108 Similar involvement of
microglia in CNS infections was suggested in other models. In a murine
model of neuro-invasive West Nile virus infection, Vasek et al. showed
that Il34−/− mice with fewer microglial cells were protected from
West Nile virus-induced synaptic terminal loss.72 Accordingly, IL-34
may probably contribute to the neurocognitive impairment in patients
recovering from neuro-invasive disease in West Nile virus infection.
In the context of HCV infection, IL-34 acts as a pro-fibrotic factor
associated with chronicity. Preisser et al. showed that IL-34 is secreted
by HCV-infected hepatocytes, and play important roles in the recruit-
ment and differentiation of monocytes into pro-fibrogenic M𝝓s, which
(1) promote type I collagen secretion by hepatic stellate cells, (2) favor
the survival of hepatic stellate cells by decreasing NK cell-mediated
cytotoxic activity, and (3) enrich injured sites with inflammatory cells
via the expression of various cytokines and chemokines. Furthermore,
IL-34-M𝝓s response to IL-13 by decreased expression of MMP-1,
13
thereby boosting their ability to promote type I collagen expression
by hepatic stellate cells.66 The pathological involvement of IL-34 in
the infection-associated cytokine network can also be observed in
influenza A virus (IAV) infection. Yu et al. described the induction of IL-
34 expression by IL-22 in IAV-infected PBMCs. Upon secretion; IL-34
seems to mediate a negative feedback loop that inhibits IL-22 produc-
tion, indicating an essential role of IL-34 in regulating the inflammatory
cascade during immune response against IAV.71
On the other hand, IL-34 has beneficial effects in the context of
other viral and bacterial infections. For example, Cheng et al. described
the ability of IL-34 to repress HBV replication in HBV-infected hep-
atocytes in vitro and in vivo when administrated intravenously into
HBV transgenic mice.73 On the contrast, Wang et al. showed recently
that serum IL-34 is elevated in HBV patients and correlates with
biomarkers of liver inflammation and fibrosis in patients with chronic
HBV.76 In an infection model of the ranavirus FV3 in Xenopus lae-
vis, Grayfer et al. showed that IL-34-derived M𝝓s exhibited potent in
vitro antiviral activity represented by robust gene expression of Arg-
1, ROS, NADPH oxidase, and type I IFN. Consistent with these antivi-
ral activities, IL-34 administration significantly prolonged survival of
FV3-infected tadpoles.117,119 More recently, Lin et al. have described
an enhanced expression of IL-34 during sepsis in patients and murine
models. Interestingly, treatment with IL-34 helped to protect mice
against polymicrobial sepsis, while IL-34 neutralization worsens sur-
vival. Intraperitoneal administration of IL-34 was found to induce the
expression of several cytokines and chemokines that recruit M𝝓s and
neutrophils such as IL-6, TNF𝛼, CXCL1, and CCL2. Thus, IL-34 may help
as an immunotherapeutic adjuvant to ameliorate survival and bacterial
clearance in sepsis.74 Additionally, Xu et al. suggested the importance
of IL-34 in inducing immune tolerance to harmless commensal fungus
such as Candida albicans. Upon stimulation with heat-killed candida,
IL-34 suppresses TNF-𝛼 production in M1-polarized M𝝓s by down-
regulating the expression of 2 critical PPRs: dectin-1 and TLR2. Thus,
the constitutive expression of IL-34 in the mucosal and dermal skin may
play a role in maintaining immune tolerance toward commensal colo-
nizing microorganisms.70
In addition to viral and bacterial infections, several studies have
suggested the involvement of IL-34 in parasite and bacterial infec-
tions, such as in gilthead sea bream (Sparus aurata) infected with
Enteromyxum leei,65 grouper infected with C. irritans,69 and large
yellow croaker (Larimichthys crocea) infected with Vibrio anguillarum
bacterium.75 As described above, IL-34 expression can be induced in
various cells following PAMPs stimulation, which indicates an impor-
tant role of IL-34 in the regulation of innate immune response against
infectious pathogens. However, the biological outcome of IL-34, favor-
able or unfavorable, seems to be controversial and depend on the infec-
tious pathogen, site, and phase of infection.
4.4 Neurologic disorders
Microglia can be activated by various triggering factors, such as in
injury, infection, or neurodegeneration. Depending on the type of
stimuli and cues at the surrounding microenvironment, microglia can
exhibit distinct activation phenotypes and may exert both beneficial
14 BAGHDADI ET AL .

and detrimental effects. IL-34 is suggested to provide potent neuro- 4.5 Cancer
protection by the modulation of microglial functions.81,82 Studies on
In the tumor microenvironment, CSF-1R regulates the function
microglial activation have indicated that in contrast to CSF-1, IL-34
and survival of tumor-associated M𝝓s (TAMs), which play crucial
results in an anti-inflammatory reparative phenotype in rodent and
roles in tumor growth, invasion, metastasis, angiogenesis, immune
human microglia.91 Given that both IL-34 and CSF-1 are expressed
suppression, and therapeutic resistance.141 Thus, the CSF-1R axis has
in the brain, a decrease in IL-34 expression is expected to result in
gained the most attention in recent cancer immunotherapeutic strate-
an imbalance in CSF-1R signaling within the brain resulting in neu-
gies, and various approaches that target this axis are currently under
roinflammation. On the other hand, chronic activation of microglia
clinical development.142–144 As a ligand of CSF-1R, several studies
by IL-34 is suggested to be accompanied with overactivation of
have focused on the role of IL-34 in cancer, showing pro-tumorigenic
myeloid cell-specific transcription factors such as PU.1 and C/EBP-
functions of IL-34 in the tumor microenvironment via multiple effects
𝛼, which enhances the expression of pro-inflammatory cytokines
on both cancer cells and myeloid cells (Fig. 4D).
and promotes neuroinflammation in chronic stages of neurological
When cancer cells are threatened such as in chemotherapy, internal
disorders (Fig. 4C).91
cascades of survival signaling are triggered to protect against cell
Several studies have unveiled the pathological involvement of IL-
death and defend against future insults. In this regard, accumulating
34 in several neurological disorders. The abnormal accumulation of
evidence has unveiled the importance of IL-34:CSF-1R axis in cancer
oA𝛽 plays critical roles in the pathogenesis of Alzheimer’s disease.
chemoresistance. CSF-1R is expressed in a subset of cancer cells or
Given that IL-34 selectively enhances the neuroprotective effects
can be induced upon exposure to chemotherapeutic agents.95,100,102
of microglia to attenuate oA𝛽 neurotoxicity, IL-34 is suggested to
Similarly, IL-34 is expressed in various types of cancer cells and can be
be pathologically involved in Alzheimer’s disease. Using human brain
induced by chemotherapy treatment.95–106 In an autocrine fashion,
clinical samples, Walker et al. have shown that IL-34 expression is
cancer cell-derived IL-34 induces strong activation of ERK1/2 and AKT
decreased in the inferior temporal gyrus in some cohorts of patients
downstream of CSF-1R, thus providing CSF-1R-expressing cancer cells
with Alzheimer’s disease.91 An interesting observation by Zhang et al.
with a critical survival signaling that help them to survive under strict
has suggested that vitamin D is capable of inducing IL-34 expres-
chemotherapeutic conditions, such as in pemetrexed-treated pleural
sion in neural cells. Consistent with this, a specific binding site for
malignant mesothelioma cells,95 doxorubicin- or cisplatin-treated
vitamin D receptor was identified within the core promoter of IL-34
lung cancer cells,100 and oxaliplatin-treated colon cancer cells.102
gene.93 Vitamin D supplementation is considered as a novel approach
Moreover, in addition to intracellular signals, the release of extracel-
to treat Alzheimer’s disease. Thus, IL-34 may provide a mechanistic
lular signals provides a way to recruit adjacent cells into an amplified
explanation of the beneficial effects of vitamin D for patients with
protective program. During cancer progression, IL-34 serves as a pow-
Alzheimer’s disease.
erful tool to reprogram M𝝓s into tumor-promoting M𝝓s in primary
Prion diseases are progressive neurodegenerative disorders caused
tumors. In solid tumors, TAMs are the most abundant immuno-
by transmissible pathogenic agents characterized by their ability to
suppressive leukocytes in the tumor microenvironment, and their
induce abnormal folding of specific normal cellular proteins called
high intensity is correlated with poor prognosis. TAMs have an M2-
prion proteins. Striking activation of microglia is frequently observed
polarized phenotype that enables them to regulate immune responses,
in prion diseases, which is suggested to play protective roles in prion
favor angiogenesis and promote tumor progression, invasion, and
pathogenesis. Consistent with this, Zhu et al. have found in a murine
metastasis.141 Early studies on the biology of IL-34 have shown
model of prion disease that the deficiency of microglia in Il34−/− mice
that IL-34-derived M𝝓s exhibit most of the phenotypic (CD14high
resulted in more astrogliosis and a significant acceleration of prion
CD163high IL-10high IL-12low CD86low ) and functional characteristics
disease progression. The scarcity of microglia at early stages of prion
(low T cell costimulatory properties, suppression of activated effector
infection or poorly understood defects in microglial functions was sug-
T cell responses) of TAMs.123 Consistent with this, embryonic stem
gested to play a role in determining disease progression.88 In this
cells-derived IL-34 contributes to polarizing bone marrow-derived
regard, it is of great interest to examine the expression levels of IL-34
M𝝓s into M2-like M𝝓s that exhibit most tumor-associated M𝝓s
in the context of prion diseases.
phenotypic and functional features, showing increased levels of
Huntingtin’s disease is an inherited neurodegeneration disorder
Arg-1, Tie-2, and TNF-𝛼 and contribute to angiogenesis and teratoma
caused by the accumulation of the abnormal protein mHTTx1. In an
progression.145 Additionally, IL-34-derived M𝝓s favor switching mem-
interesting study by Khoshnan et al., mHTTx1 was shown to create
ory T cells into Th17 cells via constitutive expression of membrane
a stressed neuronal environment that activates IKK𝛽, which in turn
IL-1𝛼. Membrane IL-1𝛼 is involved in several processes, including
promotes the aggregation of mHTTx1 and subsequent induction of
inflammation and antitumor immunity. Additionally, membrane IL-
procaspase-3 and IL-34. In turn, increased IL-34 secretion may ini-
1𝛼 exhibits pro-inflammatory and pro-angiogenetic properties and
tially signal to microglia to express neuroprotective factors and main-
increases tumor growth and metastasis. The constitutive expression
tain survival. However, chronic activation by IL-34 may lead instead to
of membrane IL-1𝛼 in IL-34-modified M𝝓s allows them to maintain
pathological activation of microglia that shows enhanced production
locally restrained and smoldering inflammation, which is required for
of inflammatory cytokines and necrotic factors, resulting in neuronal
angiogenesis and metastasis.135 Consistent with these backgrounds,
degradation and death via non-cell autonomous interactions.89
several studies have proved the ability of IL-34 to increase frequencies
BAGHDADI ET AL .
of M2-polarized TAMs with enhanced pro-tumorigenic functions
contributing importantly to tumor growth, angiogenesis, metastasis,
and therapeutic resistance.98–101 Furthermore, IL-34 is secreted
by cholangiocarcinoma stem-like subsets and educates TAMs in a
way that helps to shape tumor-supportive immune niche.104 More
recently, Han et al. have suggested the potential involvement of IL-34
in resistance to immunotherapy. In a clinical case of a patient with
melanoma that acquired resistance to anti-PD-1 immunotherapy,
IL-34 showed enhanced expression in metastatic refractory melanoma
compared to melanoma from primary sites, which correlates positively
with increased infiltration of CD163+ TAMs, which have high potential
to suppress effective antitumor immune responses.106 In addition
to TAMs, CSF-1R expression can be detected on tumor-associated
dendritic cells, tumor-associated neutrophils, and myeloid-derived
suppressor cells. Thus, it is of great interest to evaluate the impact of
IL-34 on these myeloid cells within the tumor microenvironment.
The crosstalk between IL-34 and other molecular and cellular com-
ponents of the tumor microenvironment plays important roles in
tumor progression at primary sites or in distant metastasis. For exam-
ple, IL-34 is secreted by hepatocellular carcinoma cells and enhances
the production of TGF-𝛽1 by TAMs. In turn, TAMs-derived TGF-
𝛽1 enhances IL-34 production in hepatocellular carcinoma cells by
suppressing the expression of a microRNA (miR-28-5p) that nega-
tively regulates IL-34 expression. The resulting IL-34-TGF-𝛽-mi-R-28-
5p feedback loop was suggested to modulate hepatocellular carci-
noma metastasis.101 Additionally, IL-34 was found to be produced by
giant cell tumors of bone and suggested to play a key pathogenic role
in RANKL-induced osteoclastogenesis by enriching the microenviron-
ment with bone-resorbing osteoclasts.94 Finally, IL-34 showed high
expression in some patients with brain metastasis of breast cancers,
where it may induce a phenotypic shift in resident microglia.97
IL-34 is expressed in various types of cancer, as suggested by
data from public databases such as PrognoScan and Human Protein
Atlas.146,147 The expression magnitude of IL-34 differs between can-
cers from various histological backgrounds and varies among patients
from high, weak to absent. As suggested by its potent pro-tumorigenic
functions, high expression of IL-34 correlates with poor prognosis
of cancer patients, such as in brain and lung cancers.146,147 Impor-
tantly, IL-34 showed enhanced expression in advanced stages (III and
IV) compared to early stages (I and II) in a cohort of lung cancer
patients, suggesting a correlation between IL-34 expression and tumor
progression.105 On the contrast, high expression of IL-34 is favorable in
certain types of cancer, such as in some cohorts of patients with head
and neck cancers or breast cancers.146,147 Further studies are needed
to examine whether IL-34 may have beneficial effects in some cancers,
and the related mechanisms.
In addition to CSF-1R, IL-34 exerts physiological and pathologi-
cal functions via other receptors and regulators such as PTP-𝜁 and
syndecan-1.21,22 IL-34 inhibits proliferation, motility, and clonogenic-
ity in the human glioblastoma cell line U251 via a PTP-𝜁 -mediated
mechanism.21 Additionally, IL-34 significantly increases the migra-
tion of the human acute leukemia cell line THP-1 via a syndecan-1-
mediated mechanism.22 Interestingly, IL-34 can induce the differenti-
ation of CSF-1R-expressing leukemia cells into monocyte-like cells.96
15
Hiyoshi et al. have described a role of CSF-1R mutations in hereditary
diffuse leukoencephalopathy.148 It is also of great interest to evaluate
the impact of CSF-1R mutations in IL-34- or CSF-1-expressing tumors.
Collectively, the favorable/unfavorable impact of IL-34 expression
at the tumor microenvironment can be determined by receptors and
regulators expressed by the cellular components in addition to the
molecular components available at the tumor microenvironment and
involved in the signaling network of IL-34.
5 IL-34 FROM BENCH TO BEDSIDE
5.1 IL-34 as a therapeutic tool
Based on its biological characteristics, IL-34 may show therapeutic
benefits in disease treatment. In inflammation, IL-34 may help to
attenuate inflammation and promote resolution by suppressing inflam-
matory cytokines production and accelerating the formation of
immunosuppressive immune cells such as M2-polarized M𝝓s and Tregs
at the inflammation loci. In infection, IL-34 may also help to control dis-
ease progressions such as in HBV infection and sepsis. As suggested
by Cheng et al., treatment of HBV transgenic mice (HBV-Tg C57BL/6)
with IL-34 was effective to reduce serum levels of HBV DNA, suggest-
ing a rationale for the use of IL-34 in HBV treatment.73 Additionally, Lin
et al. showed that IL-34 administration improved survival and bacterial
clearance in a mouse model of polymicrobial sepsis.74
In transplantation, IL-34 can importantly contribute to immunosup-
pression and immunotolerance required for graft survival. In a car-
diac allograft model in rats, Bézie et al. described a novel role of IL-34
in promoting allograft tolerance by the induction of CD8+ and CD4+
Tregs and inhibition of alloantibody production.136 Similarly, Zhao et al.
found that IL-34 was effective to inhibit acute rejection and prolong
the recipients’ survival by altering the polarization of Kupffer cells
polarization into an M2-phenotype in a liver transplantation model in
rats.125 Additionally, IL-34 can be used as an ex vivo cytokine for the
generation of immunosuppressive immune cells that can be utilized as
adjuvant cell therapy to prolong survival of implanted grafts. In this
regard, PSCs have obtained a great interest in cell-based regenerative
therapies due to their capacity to differentiate into various cells that
help to replenish cells lost in various conditions. To avoid immune rejec-
tion of PSCs-derived grafts, PSCs-derived immunoregulatory cells can
importantly help to prolong survival of allografts derived from the
same donor of PSCs.149,150 IL-34 has the potential to drive PSCs differ-
entiation into specific cell types such as microglial cells and can provide
a critical activation signal of CSF-1R for the generation of immuno-
suppressive M2-polarized M𝝓s.123,128,129 Thus, IL-34 may be useful in
the field of regenerative medicine in 2 ways: (1) generation of grafts
and (2) induction of allograft tolerance directly in patients, or by the
ex vivo generation of immunoregulatory cells that suppress allograft
immune responses.
IL-34 is physiologically essential for the development, maintenance,
and proper functioning of Langerhans cells and microglia in the skin
and brain, respectively.5,6 In animal studies, the deficiency of IL-34
shows no remarkable changes at the steady state but has a signifi-
16
cant impact on pathological conditions such as inflammation and viral
infection.5,6 Obviously, IL-34 may have therapeutic benefits to restore
critical physiological functions required for homeostasis at sites of
expression. Consistent with this, a correlation between reduced IL-
34 expression and disease severity can be observed in the context
of atopic dermatitis and some cohorts in patients with Alzheimer’s
disease.50,91 In atopic dermatitis, IL-34 may act as a negative reg-
ulator that inhibits the propagation of the inflammatory cascades
toward the development of active skin lesions.50 In neurological disor-
ders, IL-34 has therapeutic potential by restoring blood–brain barrier
integrity, enhancing neuroprotective functions of microglia, and pro-
moting neuro-recovery in damaged neurons.81–86 Consistent with this,
the intracerebroventricular administration of IL-34 was effective to
ameliorate impairment of associative learning and reduced oA𝛽 levels
through up-regulation of IDE and HO-1 in APP/PS1 transgenic mouse
model that resembles Alzheimer’s disease.81 These functions of IL-
34 may give a clue for new therapeutic strategies in neuroinflamma-
tory and neurodegenerative diseases such as multiple sclerosis and
Alzheimer’s disease.
5.2 IL-34 as a therapeutic target
On the contrast, targeting of IL-34 may show therapeutic benefits
in other diseases. In chronic inflammatory conditions such as inflam-
matory bowel disease, the blockade of IL-34 may help to attenuate
inflammation by suppressing the expression of inflammatory factors,
including TNF-𝛼, IL-6, and CCL20.51,52,140 In mucosal explants isolated
from patients with inflammatory bowel disease, Franzè et al. found that
IL-34 neutralization was sufficient to reduce TNF-𝛼 and IL-6.51 As an
important factor that mediates acute kidney injury and worsens subse-
quent chronic kidney disease, targeting IL-34 in the kidney and circu-
lation was suggested by Baek et al. as a potential therapeutic strategy
in kidney injuries.49 In autoimmune diseases, neutralizing IL-34 is
similarly expected to have multiple therapeutic effects in autoimmune
diseases such as RA, including (1) blocking of the inflammatory circle
caused by cytokine storm such as IL-6 and IL-17,28,36,37 (2) reduction
of pathogenic immune cell subsets such as Th17 cell,31,40,41 sensitizing
synovial fibroblasts to apoptosis,36 and (3) controlling bone erosion
and cartilage destruction caused by excessive osteoclastogenesis.27
In Sjogren’s syndrome, targeting of IL-34 was suggested as promis-
ing immunotherapy that may help to suppress the expansion of
pro-inflammatory CD14bright CD16+ monocytes in the inflamed
salivary glands.46
IL-34 shows favorable effects on controlling viral diseases such as
HBV.73 On the opposite, the IL-34 blockade can exert therapeutic
effects in other viral infections. For example, neutralizing IL-34 may
help to reduce profibrotic M𝝓s that cause liver fibrosis in the context
of HCV infection,66 suppress viral replication such as in HIV,108 and
block the inflammatory cascade in IAV.71 Furthermore, IL-34 may serve
as an attractive target for eliminating long-lived M𝝓 reservoirs of HIV
infection in the brain as well as other tissues.67,68
In cancer, IL-34 neutralizing can potentially contribute to effec-
tive antitumor responses by multiple mechanisms. In recent years,
TAMs have increasingly become recognized as an attractive target
BAGHDADI ET AL .
in cancer therapy. Depleting or repolarizing TAMs showed promis-
ing effects in preclinical models.141 As an important factor that
increases TAMs frequencies and enhances their pro-tumorigenic
functions, targeting IL-34 has a therapeutic potential in TAMs-
targeting strategies.98,100,101,104,106 Furthermore, since cancer cells
rely on IL-34-activated signaling pathways for their survival under
chemotherapeutic conditions, targeting IL-34 may help to sensi-
tize therapeutic-resistant cancer cells to cancer therapy such in
chemoresistant lung cancers, colon cancers, and malignant pleural
mesotheliomas.95,100,102 Finally, neutralizing IL-34 may show thera-
peutic benefits in controlling tumor growth, cancer-induced osteoclas-
togenesis, suppressing angiogenesis, and inhibiting cancer cell invasion
and metastasis.
In neurological disorders, the removal of microglia appeared to
have beneficial effects in some neurodegenerative disease models,
such as in stroke, cranial irradiation, toxin-induced neurotoxicity,
and amyotrophic lateral sclerosis. Indeed, most studies using CSF-
1R inhibitors have demonstrated therapeutic benefits of microglial
removal from rodent brains.91 Accordingly, targeting IL-34 may serve
as an attractive therapeutic strategy for the treatment of these disor-
ders. IL-34 also enhances the anti-inflammatory effects of microglia
and thus may have therapeutic potential in treating neurodegenera-
tive diseases that are aggravated by systemic inflammation, such as in
Parkinson disease.90
6 CONCLUDING REMARKS
In the literature, IL-34 is described as the CSF-1 “twin” cytokine.4 Both
cytokines control the biology and function of mononuclear phagocytic
lineage similarly in vitro, but specifically in vivo.11,12 IL-34 shows a con-
stitutive expression at both mRNA and protein levels in keratinocytes
and neurons and can be induced in a wide range of cells by several
stimuli. The molecular mechanisms that control IL-34 expression—
physiologically or pathologically—remain mostly unknown, and identi-
fying the responsible signaling pathways or transcription factors may
help to open new opportunities in medicine. For example, considering
its pivotal roles in Langerhans cells maintenance and microglial neuro-
protective functions, utilizing low-molecule compounds or stimulators
that induce IL-34 expression may have therapeutic potential in the skin
and neurological disorders. On the other hand, targeting IL-34 by neu-
tralizing Abs or specific inhibitors that suppress IL-34 expression in the
cellular targets may help to control other diseases such as RA, inflam-
matory bowel disease, and cancer.
The deficiency of Il34 gene showed no remarkable effects in knock-
out mice in the steady states, in contrast to Csr1r- or Csf1-deficient
mice.5,6 Thus, targeting IL-34-based strategies can be expected to
be accompanied by fewer side effects compared to CSF-1R or CSF-1
blockade. However, Il34-deficient mice showed impaired responses
to skin antigens and viral infections of the CNS.5,6 Accordingly, IL-34
targeting should be carefully considered in patients with skin or neuro-
logical disorders. On the other hand, IL-34 may serve as a therapeutic
tool in certain conditions. However, considering its critical roles in
osteoclastogenesis and immunosuppression, therapeutic strategies
BAGHDADI ET AL .
that rely on IL-34 should be considered with precautions in patients
to avoid any undesired effects such as bone destruction or unwanted
immune tolerance.
While the therapeutic potential of IL-34 has been discussed here,
for real the therapeutic effects of IL-34 targeting have been evaluated
in a very limited number of studies and restricted in most cases to
in vitro or ex vivo experiments. The realization of IL-34-based ther-
apeutic strategies is faced by the development of several effective
CSF-1R inhibitors including low-molecule compounds or neutralizing
Abs, and their rapid translation from the bench to the clinic.142–144
Indeed, the therapeutic efficacies of CSF-1R inhibitors are under
evaluation in ongoing clinical trials combined with immunotherapy,
chemotherapy, radiotherapy, and targeted therapy in tumors.142–144
Back to IL-34, CSF-1R inhibitors such as GW2580 are sufficient to
block CSF-1R-mediated biological activities of IL-34, as suggested
experimentally in vitro and ex vivo. However, CSF-1R inhibitors
showed insufficient antitumor activities in solid tumors in vivo, with a
lot of undesired side effects.142–144 Considering the severe phenotype
of Csf1r-deficient mice, CSF-1R inhibitors may result in an extended
depletion of the myeloid lineage at the systemic level.3 Additionally,
IL-34 can exert additional biological effects via other receptors such
as PTP-𝜁 and syndecan-1; 2 molecules that are importantly expressed
in tumors including but not limited to melanoma, glioblastoma, and
blood cancers.21,22 When expressed, specific targeting of IL-34
may serve as a safe and effective alternative method to control
the pathological signaling mediated by other receptors rather than
CSF-1R alone.
As a newcomer to the big family of ILs, IL-34 was introduced
as a novel cytokine that shows physiological significance on specific
myeloid cell subsets in health and critical pathological implications in
disease via a complex cellular and molecular network. From a medi-
cal point of view, IL-34 is involved in all major health issues around the
world: heart diseases, metabolic diseases, infections, and cancer. Thus,
IL-34 may serve as a potential biomarker, therapeutic target or thera-
peutic tool, which should be evaluated in future works.
AUTHORSHIP
M.B. and K.S. performed the literature review and drafted the paper.
Y.U. designed and generated illustrations. Y.U., N.Hama, T.K., N.Han,
and H.W. contributed to the revision of the manuscript.
ACKNOWLEDGMENTS
This work was supported in part by Japan Agency for Medical
Research and Development AMED (K. S.), Japan Society for the Pro-
motion of Science (JSPS) Grant-in-Aid for Young Scientists (grant no.
18K15261, M.B.), and Joint Research Program of Institute for Genetic
Medicine, Hokkaido University (The Liason Laboratory in the Center
for Infection-Associated Cancer). Figures and illustrations were pro-
duced using Servier Medical Art.
DISCLOSURE
The authors declare no conflicts of interest.
17
REFERENCES
1. Chow V, Brown BD, Merad M. Studying the mononuclear phagocyte
system in the molecular age. Nat Rev Immunol. 2011;11:788–798.
2. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold
Spring Harb Perspect Biol. 2014;6:a021857.
3. Dai XM, Ryan GR, Hapel AJ, et al. Targeted disruption of the mouse
colony-stimulating factor 1 receptor gene results in osteopetrosis,
mononuclear phagocyte deficiency, increased primitive progenitor
cell frequencies, and reproductive defects. Blood. 2002;99:111–120.
4. Lin H, Lee E, Hestir K, et al. Discovery of a cytokine and its recep-
tor by functional screening of the extracellular proteome. Science.
2008;320:807–811.
5. Wang Y, Szretter KJ, Vermi W, et al. IL-34 is a tissue-restricted lig-
and of CSF1R required for the development of Langerhans cells and
microglia. Nat Immunol. 2012;13:753–760.
6. Greter M, Lelios I, Pelczar P, et al. Stroma-derived interleukin-34 con-
trols the development and maintenance of Langerhans cells and the
maintenance of microglia. Immunity. 2012;37:1050–1060.
7. Wei S, Nandi S, Chitu V, et al. Functional overlap but differential
expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated reg-
ulation of myeloid cells. J Leukoc Biol. 2010;88:495–505.
8. Nakamichi Y, Mizoguchi T, Arai A, et al. Spleen serves as a reservoir
of osteoclast precursors through vitamin D-induced IL-34 expres-
sion in osteopetrotic op/op mice. Proc Natl Acad Sci USA. 2012;109:
10006–10011.
9. Droin N, Solary E. Editorial: cSF1R, CSF-1, and IL-34, a “ménage à
trois” conserved across vertebrates. J Leukoc Biol. 2010;87:745–747.
10. Zelante T, Ricciardi-Castagnoli P. The yin-yang nature of CSF1R-
binding cytokines. Nat Immunol. 2012;13:717–719.
11. Guillonneau C, Bézie S, Anegon I. Immunoregulatory properties of
the cytokine IL-34. Cell Mol Life Sci. 2017;74:2569–2586.
12. Baghdadi M, Endo H, Tanaka Y, Wada H, Seino KI. Interleukin 34, from
pathogenesis to clinical applications. Cytokine. 2017;99:139–147.
13. Masteller EL, Wong BR. Targeting IL-34 in chronic inflammation. Drug
Discov Today. 2014;19:1212–1216.
14. Liu H, Leo C, Chen X, et al. The mechanism of shared but distinct
CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1.
Biochim Biophys Acta. 2012;1824:938–945.
15. Ma X, Lin WY, Chen Y, et al. Structural basis for the dual recog-
nition of helical cytokines IL-34 and CSF-1 by CSF-1R. Structure.
2012;20:676–687.
16. Felix J, Elegheert J, Gutsche I, et al. Human IL-34 and CSF-1 estab-
lish structurally similar extracellular assemblies with their common
hematopoietic receptor. Structure. 2013;21:528–539.
17. Nakamichi Y, Udagawa N, Takahashi N. IL-34 and CSF-1: similarities
and differences. J Bone Miner Metab. 2013;31:486–495.
18. Kryshtafovych A, Moult J, Bales P, et al. Challenging the state of the
art in protein structure prediction: highlights of experimental target
structures for the 10th Critical Assessment of Techniques for Protein
Structure Prediction Experiment CASP10. Proteins. 2014;2:26–42.
19. Felix J, De Munck S, Verstraete K, et al. Structure and assembly mech-
anism of the signaling complex mediated by human CSF-1. Structure.
2015;23:1621–1631.
20. Ségaliny AI, Brion R, Brulin B, et al. IL-34 and M-CSF form a novel het-
eromeric cytokine and regulate the M-CSF receptor activation and
localization. Cytokine. 2015;76:170–181.
21. Nandi S, Cioce M, Yeung YG, et al. Receptor-type protein-tyrosine
phosphatase 𝜁 is a functional receptor for interleukin-34. J Biol Chem.
2013;288:21972–21986.
18
22. Segaliny AI, Brion R, Mortier E, et al. Syndecan-1 regulates
the biological activities of interleukin-34. Biochim Biophys Acta.
2015;1853:1010–1021.
23. Boulakirba S, Pfeifer A, Mhaidly R, et al. IL-34 and CSF-1 display an
equivalent macrophage differentiation ability but a different polar-
ization potential. Sci Rep. 2018;8:256.
24. Garceau V, Balic A, Garcia-Morales C, et al. The development and
maintenance of the mononuclear phagocyte system of the chick is
controlled by signals from the macrophage colony-stimulating factor
receptor. BMC Biol. 2015;13:12.
25. Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the
human proteome. Science. 2015;347:1260419.
26. Chemel M, Le Goff B, Brion R, et al. Interleukin 34 expression is asso-
ciated with synovitis severity in rheumatoid arthritis patients. Ann
Rheum Dis. 2012;71:150–154.
27. Hwang SJ, Choi B, Kang SS, et al. Interleukin-34 produced by human
fibroblast-like synovial cells in rheumatoid arthritis supports osteo-
clastogenesis. Arthritis Res Ther. 2012;14:R14.
28. Boström EA, Lundberg P. The newly discovered cytokine IL-34 is
expressed in gingival fibroblasts, shows enhanced expression by pro-
inflammatory cytokines, and stimulates osteoclast differentiation.
PLoS One. 2013;8:e81665.
29. Clavel G, Thiolat A, Boissier MC. Interleukin newcomers creating
new numbers in rheumatology: IL-34 to IL-38. Joint Bone Spine.
2013;80:449–453.
30. Moon SJ, Hong YS, Ju JH, Kwok SK, Park SH, Min JK. Increased
levels of interleukin 34 in serum and synovial fluid are associated
with rheumatoid factor and anticyclic citrullinated peptide antibody
titers in patients with rheumatoid arthritis. J Rheumatol. 2013;40:
1842–1849.
31. Tian Y, Shen H, Xia L, Lu J. Elevated serum and synovial fluid levels of
interleukin-34 in rheumatoid arthritis: possible association with dis-
ease progression via interleukin-17 production. J Interferon Cytokine
Res. 2013;33:398–401.
32. Chang SH, Choi BY, Choi J, et al. Baseline serum interleukin-34 lev-
els independently predict radiographic progression in patients with
rheumatoid arthritis. Rheumatol Int. 2015;35:71–79.
33. Ding R, Li P, Song D, Zhang X, Bi L. Predictors of response to TNF-
𝛼 antagonist therapy in Chinese rheumatoid arthritis. Clin Rheumatol.
2015;34:1203–1210.
34. Zhang F, Ding R, Li P, et al. Interleukin-34 in rheumatoid arthri-
tis: potential role in clinical therapy. Int J Clin Exp Med. 2015;8:
7809–7815.
35. Garcia S, Hartkamp LM, Malvar-Fernandez B, et al. Colony-
stimulating factor (CSF) 1 receptor blockade reduces inflammation
in human and murine models of rheumatoid arthritis. Arthritis Res
Ther. 2016;18:75.
36. Yang S, Jiang S, Wang Y, Tu S, Wang Z, Chen Z. Interleukin 34 upreg-
ulation contributes to the increment of MicroRNA 21 expression
through STAT3 activation associated with disease activity in rheuma-
toid arthritis. J Rheumatol. 2016;43:1312–1319.
37. Zhou RP, Wu XS, Xie YY, et al. Functions of interleukin-34 and
its emerging association with rheumatoid arthritis. Immunology.
2016;149:362–373.
38. Chemel M, Brion R, Segaliny AI, et al. Bone morphogenetic pro-
tein 2 and transforming growth factor 𝛽1 inhibit the expression of
the proinflammatory cytokine IL-34 in rheumatoid arthritis synovial
fibroblasts. Am J Pathol. 2017;187:156–162.
39. Galligan CL, Fish EN. Interleukin-34 promotes fibrocyte proliferation.
J Interferon Cytokine Res. 2017;37:440–448.
BAGHDADI ET AL .
40. Wang B, Ma Z, Wang M, et al. IL-34 upregulated Th17 production
through increased IL-6 expression by rheumatoid fibroblast-like syn-
oviocytes. Mediators Inflamm. 2017;2017:1567120.
41. Wang B, Tang Y, Sun X, et al. Increased IL-6 expression on THP-1 by
IL-34 stimulation up-regulated rheumatoid arthritis Th17 cells. Clin
Rheumatol. 2018;37:127–137.
42. Zhang L, Cui M, Ding L, Xia L, Lu J, Shen H. Interleukin-34 aggra-
vates the severity of arthritis in collagen-induced arthritis collagen-
induced arthritis mice by inducing interleukin-17 production. J Inter-
feron Cytokine Res. 2018;38:221–225.
43. Bethunaickan R, Berthier CC, Zhang W, Kretzler M, Davidson A.
Comparative transcriptional profiling of 3 murine models of SLE
nephritis reveals both unique and shared regulatory networks. PLoS
One. 2013;8:e77489.
44. Wang H, Cao J, Lai X. Serum interleukin-34 levels are elevated in
patients with systemic lupus erythematosus. Molecules. 2016;22:E35.
45. Xie HH, Shen H, Zhang L, Cui MY, Xia LP, Lu J. Elevated serum
interleukin-34 level in patients with systemic lupus erythematosus is
associated with disease activity. Sci Rep. 2018;8:3462.
46. Ciccia F, Alessandro R, Rodolico V, et al. IL-34 is overexpressed in
the inflamed salivary glands of patients with Sjogren’s syndrome and
is associated with the local expansion of pro-inflammatory CD14
(bright) CD16+ monocytes. Rheumatology. 2013;52:1009–1017.
47. Li J, Liu L, Rui W, et al. New interleukins in psoriasis and pso-
riatic arthritis patients: the possible roles of interleukin-33 to
interleukin-38 in disease activities and bone erosions. Dermatology.
2017;233:37–46.
48. Li Z, Jin D, Wu Y, et al. Increased serum interleukin-34 in patients with
coronary artery disease. J Int Med Res. 2012;40:1866–1870.
49. Baek JH, Zeng R, Weinmann-Menke J, et al. IL-34 mediates acute
kidney injury and worsens subsequent chronic kidney disease. J Clin
Invest. 2015;125:3198–3214.
50. Esaki H, Ewald DA, Ungar B, et al. Identification of novel immune and
barrier genes in atopic dermatitis by means of laser capture microdis-
section. J Allergy Clin Immunol. 2015;135:153–163.
51. Franzè E, Monteleone I, Cupi ML, et al. Interleukin-34 sustains inflam-
matory pathways in the gut. Clin Sci. 2015;129:271–280.
52. Zwicker S, Martinez GL, Bosma M, et al. Interleukin 34: a new mod-
ulator of human and experimental inflammatory bowel disease. Clin
Sci. 2015;129:281–290.
53. Fan Q, Yan X, Zhang H, et al. IL-34 is associated with the presence and
severity of renal dysfunction and coronary artery disease in patients
with heart failure. Sci Rep. 2016;6:39324.
54. Ma N, Qu L, Xu LY, Yu YQ, Qiu LH. Expression of IL-34 in chronic peri-
apical lesions and its clinical significance. Shanghai Kou Qiang Yi Xue.
2016;25:53–57.
55. Sanchez-Niño MD, Sanz AB, Ortiz A. Chronicity following ischaemia-
reperfusion injury depends on tubular-macrophage crosstalk involv-
ing two tubular cell-derived CSF-1R activators: CSF-1 and IL-34.
Nephrol Dial Transplant. 2016;31:1409–1416.
56. San Segundo D, Ruiz P, Irure J, et al. Serum levels of interleukin-
34 during acute rejection in liver transplantation. Transplant Proc.
2016;48:2977–2979.
57. Shoji H, Yoshio S, Mano Y, et al. Interleukin-34 as a fibroblast-derived
marker of liver fibrosis in patients with non-alcoholic fatty liver dis-
ease. Sci Rep. 2016;6:28814.
58. Wang Y, Bugatti M, Ulland TK, Vermi W, Gilfillan S, Colonna M.
Nonredundant roles of keratinocyte-derived IL-34 and neutrophil-
derived CSF1 in Langerhans cell renewal in the steady state and dur-
ing inflammation. Eur J Immunol. 2016;46:552–559.
BAGHDADI ET AL .
59. Jodeleit H, Palamides P, Beigel F, et al. Design and validation of a
disease network of inflammatory processes in the NSG-UC mouse
model. J Transl Med. 2017;15:265.
60. Martinez GL, Majster M, Bjurshammar N, Johannsen A, Figueredo
CM, Boström EA. Salivary colony stimulating factor-1 and
interleukin-34 in periodontal disease. J Periodontol. 2017;8:
e140-e149.
61. Tao R, Fan Q, Zhang H, et al. Prognostic significance of interleukin-
34 (IL-34) in patients with chronic heart failure with or without renal
insufficiency. J Am Heart Assoc. 2017;6:e004911.
62. Guruprasad CN, Pradeep AR. Interleukin-34 levels in gingival
crevicular fluid and plasma in periodontal health and disease
with and without type-2 diabetes mellitus. J Investig Clin Dent.
2018:e12317.
63. Baghdadi M, Ishikawa K, Endo H, et al. Enhanced expression of IL-34
in an inflammatory cyst of the submandibular gland: a case report.
Inflammation and Regeneration. 2018. doi.
64. Covaleda L, Fuller FJ, Payne SL. EIAV S2 enhances pro-inflammatory
cytokine and chemokine response in infected macrophages. Virology.
2010;397:217–223.
65. Pérez-Cordón G, Estensoro I, Benedito-Palos L, Calduch-Giner JA,
Sitjà-Bobadilla A, Pérez-Sánchez J. Interleukin gene expression is
strongly modulated at the local level in a fish-parasite model. Fish
Shellfish Immunol. 2014;37:201–208.
66. Preisser L, Miot C, Le Guillou-Guillemette H, et al. IL-34 and
macrophage colony-stimulating factor are overexpressed in hep-
atitis C virus fibrosis and induce profibrotic macrophages that
promote collagen synthesis by hepatic stellate cells. Hepatology.
2014;60:1879–1890.
67. Gerngross L, Fischer T. Evidence for cFMS signaling in HIV pro-
duction by brain macrophages and microglia. J Neurovirol. 2015;21:
249–256.
68. Gerngross L, Lehmicke G, Belkadi A, Fischer T. Role for cFMS in
maintaining alternative macrophage polarization in SIV infection:
implications for HIV neuropathogenesis. J Neuroinflammation. 2015;
25:58. 12.
69. Mo ZQ, Li YW, Zhou L, Li AX, Luo XC, Dan XM. Grouper (Epinephelus
coioides) IL-34/MCSF2 and MCSFR1/MCSFR2 were involved in
mononuclear phagocytes activation against Cryptocaryon irritans
infection. Fish Shellfish Immunol. 2015;43:142–149.
70. Xu R, Sun HF, Williams DW, et al. IL-34 suppresses Candida albicans
induced TNF𝛼 production in M1 macrophages by downregulating
expression of Dectin-1 and TLR2. J Immunol Res. 2015;2015:328146.
71. Yu G, Bing Y, Zhu S, et al. Activation of the interleukin-34 inflamma-
tory pathway in response to influenza A virus infection. Am J Med Sci.
2015;349:145–150.
72. Vasek MJ, Garber C, Dorsey D, et al. A complement-microglial
axis drives synapse loss during virus-induced memory impairment.
Nature. 2016;534:538–543.
73. Cheng ST, Tang H, Ren JH, Chen X, Huang AL, Chen J. Interleukin-34
inhibits hepatitis B virus replication in vitro and in vivo. PLOS ONE.
2017;12:e0179605.
74. Lin X, Luo H, Yan X, et al. Interleukin-34 ameliorates survival and
bacterial clearance in polymicrobial sepsis. Crit Care Med. 2018;46:
e584-e590.
75. Wang L, Jiang L, Wu C, Lou B. Molecular characterization and expres-
sion analysis of large yellow croaker (Larimichthys crocea) interleukin-
12A, 16 and 34 after poly I:C and Vibrio anguillarum challenge. Fish
Shellfish Immunol. 2018;74:84–93.
19
76. Wang YQ, Cao WJ, Gao YF, Ye J, Zou GZ. Serum interleukin-
34 level can be an indicator of liver fibrosis in patients with
chronic hepatitis B virus infection. World J Gastroenterol. 2018;24:
1312–1320.
77. Below JE, Gamazon ER, Morrison JV, et al. Genome-wide associa-
tion and meta-analysis in populations from Starr County, Texas, and
Mexico City identify type 2 diabetes susceptibility loci and enrich-
ment for expression quantitative trait loci in top signals. Diabetologia.
2011;54:2047–2055.
78. Chang EJ, Lee SK, Song YS, et al. IL-34 is associated with obesity,
chronic inflammation, and insulin resistance. J Clin Endocrinol Metab.
2014;99:E1263–E1271.
79. Liao LN, Chen CC, Wu FY, et al. Identified single-nucleotide
polymorphisms and haplotypes at 16q22.1 increase diabetic
nephropathy risk in Han Chinese population. BMC Genet. 2014;
15:113.
80. Zorena K, Jachimowicz-Duda O, Wąż P. The cut-off value for inter-
leukin 34 as an additional potential inflammatory biomarker for
the prediction of the risk of diabetic complications. Biomarkers.
2016;21:276–282.
81. Mizuno T, Doi Y, Mizoguchi H, et al. Interleukin-34 selectively
enhances the neuroprotective effects of microglia to attenu-
ate oligomeric amyloid-𝛽 neurotoxicity. Am J Pathol. 2011;179:
2016–2027.
82. Ma D, Doi Y, Jin S, et al. TGF-𝛽 induced by interleukin-34-
stimulated microglia regulates microglial proliferation and attenu-
ates oligomeric amyloid 𝛽 neurotoxicity. Neurosci Lett. 2012;529:
86–91.
83. Gómez-Nicola D, Fransen NL, Suzzi S, Perry VH. Regulation of
microglial proliferation during chronic neurodegeneration. J Neu-
roSci. 2013;33:2481–2493.
84. Luo J, Elwood F, Britschgi M, et al. Colony-stimulating factor 1 recep-
tor (CSF1R) signaling in injured neurons facilitates protection and
survival. J Exp Med. 2013;210:157–172.
85. Jin S, Sonobe Y, Kawanokuchi J, et al. Interleukin-34 restores blood-
brain barrier integrity by upregulating tight junction proteins in
endothelial cells. PLoS One. 2014;9:e115981.
86. Chitu V, Gokhan Ş, Nandi S, Mehler MF, Stanley ER. Emerging roles
for CSF-1 receptor and its ligands in the nervous system. Trends Neu-
rosci. 2016;39:378–393.
87. Okubo M, Yamanaka H, Kobayashi K, et al. Macrophage colony stim-
ulating factor derived from injured primary afferent induces prolif-
eration of spinal microglia and neuropathic pain in rats. PLoS One.
2016;11:e0153375.
88. Zhu C, Herrmann US, Falsig J, et al. A neuroprotective role for
microglia in prion diseases. J Exp Med. 2016;213:1047–1059.
89. Khoshnan A, Sabbaugh A, Calamini B, et al. IKK𝛽 and mutant hunt-
ingtin interactions regulate the expression of IL-34: implications
for microglial-mediated neurodegeneration in HD. Hum Mol Genet.
2017;26:4267–4277.
90. Kim J, Jeong YH, Lee EJ, Park JS, Seo H, Kim HS. Suppression
of neuroinflammation by matrix metalloproteinase-8 inhibitor in
aged normal and LRRK2 G2019S Parkinson’s disease model mice
challenged with lipopolysaccharide. Biochem Biophys Res Commun.
2017;493:879–886.
91. Walker DG, Tang TM, Lue LF. Studies on colony stimulating factor
receptor-1 and ligands colony stimulating factor-1 and interleukin-
34 in Alzheimer’s disease brains and human microglia. Front Aging
Neurosci. 2017;9:244.
20
92. Xing C, Lo EH. Help-me signaling: non-cell autonomous mech-
anisms of neuroprotection and neurorecovery. Prog Neurobiol.
2017;152:181–199.
93. Zhang D, Li M, Dong Y, et al. 1𝛼, 25-Dihydroxyvitamin D3 up-
regulates IL-34 expression in SH-SY5Y neural cells. Innate Immun.
2017;23:584–591.
94. Baud’huin M, Renault R, Charrier C, et al. Interleukin-34 is expressed
by giant cell tumours of bone and plays a key role in RANKL-induced
osteoclastogenesis. J Pathol. 2010;221:77–86.
95. Cioce M, Canino C, Goparaju C, Yang H, Carbone M, Pass HI.
Autocrine CSF-1R signaling drives mesothelioma chemoresistance
via AKT activation. Cell Death Dis. 2014;5:e1167.
96. Booker BE, Clark RS, Pellom ST, Adunyah SE. Interleukin-34 induces
monocytic-like differentiation in leukemia cell lines. Int J Biochem Mol
Biol. 2015;6:1–16.
97. Rietkötter E, Bleckmann A, Bayerlová M, et al. Anti-CSF-1 treat-
ment is effective to prevent carcinoma invasion induced by
monocyte-derived cells but scarcely by microglia. Oncotarget. 2015;6:
15482–15493.
98. Ségaliny AI, Mohamadi A, Dizier B, et al. Interleukin-34 promotes
tumor progression and metastatic process in osteosarcoma through
induction of angiogenesis and macrophage recruitment. Int J Cancer.
2015;137:73–85.
99. Wang B, Xu W, Tan M, Xiao Y, Yang H, Xia TS. Integrative genomic
analyses of a novel cytokine, interleukin-34 and its potential role in
cancer prediction. Int J Mol Med. 2015;35:92–102.
100. Baghdadi M, Wada H, Nakanishi S, et al. Chemotherapy-induced IL34
enhances immunosuppression by tumor-associated macrophages
and mediates survival of chemoresistant lung cancer cells. Cancer Res.
2016;76:6030–6042.
101. Zhou SL, Hu ZQ, Zhou ZJ, et al. miR-28-5p-IL-34-macrophage feed-
back loop modulates hepatocellular carcinoma metastasis. Hepatol-
ogy. 2016;63:1560–1575.
102. Franzè E, Dinallo V, Rizzo A, et al. Interleukin-34 sustains pro-
tumorigenic signals in colon cancer tissue. Oncotarget. 2017;9:
3432–3445.
103. Gao X, Zhang S, Xu Z, et al. Effects of interleukin-34 expressed by
human bone marrow derived mesenchymal stem cells on THP-1 cells.
Sheng Wu Gong Cheng Xue Bao. 2017;33:642–652.
104. Raggi C, Correnti M, Sica A, et al. Cholangiocarcinoma stem-
like subset shapes tumor-initiating niche by educating associated
macrophages. J Hepatol. 2017;66:102–115.
105. Baghdadi M, Endo H, Takano A, et al. High co-expression of IL-34 and
M-CSF correlates with tumor progression and poor survival in lung
cancers. Sci Rep. 2018;8:418.
106. Han N, Baghdadi M, Ishikawa K, et al. Enhanced IL-34 expres-
sion in Nivolumab-resistant metastatic melanoma. Inflamm Regen.
2018;38:3.
107. Hong S, Li R, Xu Q, Secombes CJ, Wang T. Two types of TNF-𝛼
exist in teleost fish: phylogeny, expression, and bioactivity analysis
of type-II TNF-𝛼3 in rainbow trout Oncorhynchus mykiss. J Immunol.
2013;191:5959–5972.
108. Chihara T, Suzu S, Hassan R, et al. IL-34 and M-CSF share the receptor
Fms but are not identical in biological activity and signal activation.
Cell Death Differ. 2010;17:1917–1927.
109. Kawabe M, Ohyama H, Kato-Kogoe N, et al. Expression of
interleukin-34 and colony stimulating factor-1 in the stimulated
periodontal ligament cells with tumor necrosis factor-𝛼. Med Mol
Morphol. 2015;48:169–176.
BAGHDADI ET AL .
110. Schuster C, Mildner M, Mairhofer M, et al. Human embryonic epider-
mis contains a diverse Langerhans cell precursor pool. Development.
2014;141:807–815.
111. Lindau R, Mehta RB, Lash GE, et al. Interleukin-34 is present
at the fetal-maternal interface and induces immunoregulatory
macrophages of a decidual phenotype in vitro. Human Reprod.
2018;33:588–599.
112. Garceau V, Smith J, Paton IR, et al. Pivotal advance: avian colony-
stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 recep-
tor genes and gene products. J Leukoc Biol. 2010;87:753–764.
113. Neves F, Abrantes J, Steinke JW, Esteves PJ. Maximum-likelihood
approaches reveal signatures of positive selection in IL genes in mam-
mals. Innate Immun. 2014;20:184–191.
114. Gow DJ, Garceau V, Kapetanovic R, et al. Cloning and expression of
porcine colony stimulating factor-1 (CSF-1) and colony stimulating
factor-1 receptor (CSF-1R) and analysis of the species specificity of
stimulation by CSF-1 and Interleukin 34. Cytokine. 2012;60:793–805.
115. Gow DJ, Garceau V, Pridans C, et al. Cloning and expression of
feline colony stimulating factor receptor (CSF-1R) and analysis of the
species specificity of stimulation by colony stimulating factor-1 (CSF-
1) and interleukin-34 (IL-34). Cytokine. 2013;61:630–638.
116. Wang T, Kono T, Monte MM, et al. Identification of IL-34 in
teleost fish: differential expression of rainbow trout IL-34, MCSF1
and MCSF2, ligands of the MCSF receptor. Mol Immunol. 2013;53:
398–409.
117. Grayfer L, Robert J. Divergent antiviral roles of amphibian (Xeno-
pus laevis) macrophages elicited by colony-stimulating factor-1 and
interleukin-34. J Leukoc Biol. 2014;96:1143–1153.
118. Venkatesh B, Lee AP, Ravi V, et al. Elephant shark genome pro-
vides unique insights into gnathostome evolution. Nature. 2014;505:
174–179.
119. Grayfer L, Robert J. Distinct functional roles of amphibian (Xeno-
pus laevis) colony-stimulating factor-1- and interleukin-34-derived
macrophages. J Leukoc Biol. 2015;98:641–649.
120. Wang Y, Colonna M. Interkeukin-34, a cytokine crucial for the dif-
ferentiation and maintenance of tissue resident macrophages and
Langerhans cells. Eur J Immunol. 2014;44:1575–1581.
121. Nandi S, Gokhan S, Dai XM, et al. The CSF-1 receptor ligands IL-34
and CSF-1 exhibit distinct developmental brain expression patterns
and regulate neural progenitor cell maintenance and maturation. Dev
Biol. 2012;367:100–113.
122. Tríbulo P, Siqueira LGB, Oliveira LJ, Scheffler T, Hansen PJ. Identifica-
tion of potential embryokines in the bovine reproductive tract. J Dairy
Sci. 2018;101:690–704.
123. Foucher ED, Blanchard S, Preisser L, et al. IL-34 induces the differen-
tiation of human monocytes into immunosuppressive macrophages,
antagonistic effects of GM-CSF and IFN𝛾. PLoS One. 2013;
8:e56045.
124. Barve RA, Zack MD, Weiss D, Song RH, Beidler D, Head RD. Tran-
scriptional profiling and pathway analysis of CSF-1 and IL-34 effects
on human monocyte differentiation. Cytokine. 2013;63:10–17.
125. Zhao Z, Pan G, Tang C, et al. IL-34 inhibits acute rejection of rat liver
transplantation by inducing Kupffer cell M2 polarization. Transplanta-
tion. 2018;102:e265-e274.
126. Chen Z, Buki K, Vääräniemi J, Gu G, Väänänen HK. The critical role of
IL-34 in osteoclastogenesis. PLoS One. 2011;6:e18689.
127. Ohgidani M, Kato TA, Setoyama D, et al. Direct induction of ramified
microglia-like cells from human monocytes: dynamic microglial dys-
function in Nasu-Hakola disease. Sci Rep. 2014;4:4957.
BAGHDADI ET AL .
128. Ohgidani M, Kato TA, Kanba S. Introducing directly induced
microglia-like (iMG) cells from fresh human monocytes: a novel trans-
lational research tool for psychiatric disorders. Front Cell Neurosci.
2015;27:184. 9.
129. Amos PJ, Fung S, Case A, et al. Modulation of hematopoietic
lineage specification impacts TREM2 expression in microglia-
like cells derived from human stem cells. ASN Neuro. 2017;
9:1759091417716610.
130. Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB,
Barres BA. Diverse requirements for microglial survival, specifica-
tion, and function revealed by defined-medium cultures. Neuron.
2017;94:759–773.
131. Yamane F, Nishikawa Y, Matsui K, et al. CSF-1 receptor-mediated dif-
ferentiation of a new type of monocytic cell with B cell-stimulating
activity: its selective dependence on IL-34. J Leukoc Biol. 2014;95:
19–31.
132. Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB.
Macrophage-colony stimulating factor and interleukin-34 induce
chemokines in human whole blood. Cytokine. 2010;52:215–220.
133. Eda H, Shimada H, Beidler DR, Monahan JB. Proinflammatory
cytokines, IL-1𝛽 and TNF-𝛼, induce expression of interleukin-34
mRNA via JNK- and p44/42 MAPK-NF-𝜅B pathway but not p38 path-
way in osteoblasts. Rheumatol Int. 2011;31:1525–1530.
134. Yu Y, Yang D, Qiu L, Okamura H, Guo J, Haneji T. Tumor necro-
sis factor-𝛼 induces interleukin-34 expression through nuclear
factor-𝜅B activation in MC3T3-E1 osteoblastic cells. Mol Med Rep.
2014;10:1371–1376.
135. Foucher ED, Blanchard S, Preisser L, et al. IL-34- and M-CSF-induced
macrophages switch memory T cells into Th17 cells via membrane IL-
1𝛼. Eur J Immunol. 2015;45:1092–1102.
136. Bézie S, Picarda E, Ossart J, et al. IL-34 is a Treg-specific cytokine and
mediates transplant tolerance. J Clin Invest. 2015;125:3952–3964.
137. Kim JI, Turka LA. Transplant tolerance: a new role for IL-34. J Clin
Invest. 2015;125:3751–3753.
138. Bézie S, Meistermann D, Boucault L, et al. Ex Vivo Expanded
Human Non-Cytotoxic CD8+ CD45RClow/- Tregs efficiently delay
skin graft rejection and GVHD in humanized mice. Front Immunol.
2018;8:2014.
139. Zwicker S, Bureik D, Bosma M, Martinez GL, Almer S, Boström
EA. Receptor-type protein-tyrosine phosphatase 𝜁 and colony
View publication stats
21
stimulating factor-1 receptor in the intestine: cellular expression and
cytokine- and chemokine responses by interleukin-34 and colony
stimulating factor-1. PLoS One. 2016;11:e0167324.
140. Franzè E, Marafini I, De Simone V, et al. Interleukin-34 induces
cc-chemokine ligand 20 in gut epithelial cells. J Crohns Colitis.
2016;10:87–94.
141. Noy R, Pollard JW. Tumor-associated macrophages: from mecha-
nisms to therapy. Immunity. 2017;41:49–61.
142. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger
D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer
therapy. J Immunother Cancer. 2017;5:53.
143. Peyraud F, Cousin S, Italiano A. CSF-1R inhibitor development: cur-
rent clinical status. Curr Oncol Rep. 2017;19:70.
144. Kumari A, Silakari O, Singh RK. Recent advances in colony stimulating
factor-1 receptor / c-FMS as an emerging target for various therapeu-
tic implications. Biomed Pharmacother. 2018;103:662–679.
145. Chen T, Wang X, Guo L, et al. Embryonic stem cells promoting
macrophage survival and function are crucial for teratoma develop-
ment. Front Immunol. 2014;5:275.
146. Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for
meta-analysis of the prognostic value of genes. BMC Med Genomics.
2009;2:18.
147. Uhlen M, Zhang C, Lee S, et al. A pathology atlas of the human cancer
transcriptome. Science. 2017;357:6352.
148. Hiyoshi M, Hashimoto M, Yukihara M, Bhuyan F, Suzu S. M-CSF
receptor mutations in hereditary diffuse leukoencephalopathy with
spheroids impair not only kinase activity but also surface expression.
Biochem Biophys Res Commun. 2013;440:589–593.
149. Kudo H, Wada H, Sasaki H, et al. Induction of macrophage-like
immunosuppressive cells from mouse ES cells that contribute to pro-
long allogeneic graft survival. PLoS One. 2014;9:e111826.
150. Sasaki H, Wada H, Baghdadi M, et al. New immunosuppressive cell
therapy to prolong survival of induced pluripotent stem cell-derived
allografts. Transplantation. 2015;99:2301–2310.
How to cite this article: Baghdadi M, Umeyama Y, Hama N,
et al. Interleukin 34, a comprehensive review. J Leukoc Biol.
2018;1–21. https://doi.org/10.1002/JLB.MR1117-457R