International Immunopharmacology 10 (2010) 13251334

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International Immunopharmacology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n t i m p

Review

Neutrophils: Cinderella of innate immune system

V. Kumar a,, A. Sharma b
a
Department of Pediatrics, Faculty of Medicine, Sainte-Justine Hospital, University of Montreal, Montreal, Canada
b
Department of Microbiology, Dr. Y.S. Parmar University, Solan, India

a r t i c l e i n f o a b s t r a c t

Article history: Neutrophils are the rst line of innate immune defense against infectious diseases. However, since their
Received 18 June 2010 discovery by Elie Metchnikoff, they have always been considered tissue-destructive cells responsible for
Received in revised form 18 August 2010 inammatory tissue damage occurring during acute infections. Now, extensive research in the eld of
Accepted 20 August 2010
neutrophil cell biology and their role skewing the immune response in various infections or inammatory
disorders revealed their importance in the regulation of immune response. Along with releasing various
Keywords:
Neutrophils
antimicrobial molecules, neutrophils also release neutrophil extracellular traps (NETs) for the containment
Macrophages of infection and inammation. Activated neutrophils provide signals for the activation and maturation of
Dendritic cells macrophages as well as dendritic cells. Neutrophils are also involved in the regulation of T-cell immune
T cells response against various pathogens and tumor antigens. Thus, the present review is intended to highlight
Innate immunity the emerging role of neutrophils in the regulation of both innate and adaptive immunity during acute
Adaptive immunity infectious or inammatory conditions.
2010 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1325
2. Neutrophils in acute bacterial infections and inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326
3. Antimicrobial activity of neutrophils in acute infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326
4. Neutrophil extracellular traps (NETs) in immunity and infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326
5. Neutrophil and macrophage interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327
6. Neutrophil and dendritic cell (DC) interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327
7. Neutrophils as inducers of adaptive immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329
8. Neutrophils and Th17 cells cross-talk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330
9. Myeloid-derived suppressor cells (MDSCs) and suppression of T cell immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . 1330
10. Future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331

1. Introduction natural killer (NK) cells and dendritic cells (DCs)], various soluble
mediators secreted by these cells and complement system. These cells
The human innate immune system is comprised of various and mediators together comprise an effective defense system against
immune cells [i.e. neutrophils, monocytes/macrophages, mast cells, pathogenic microorganisms as well as xenobiotics. Neutrophils are

Abbreviations: DPPI, dipeptidyl peptidase I; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular trap; SCAMP, secretory
carrier membrane protein; VAMP-2, vesicle-associated membrane protein-2; uPAR, urokinase type plasminogen-activating receptor; PLS, Papillon-Lefevre syndrome; PMA, phorbol
myristate; OMV, outer membrane vesicle; fMLP, formyl-methionyl-leucyl-phenylalanine; HMG-B1, high mobility group box 1 protein; HNP-1 or HNP-2, human neutrophil Peptide-1
or-2; mCRAMP, mouse cathelin-related antimicrobial peptide; MAPK, mitogen activated protein kinase; RAGE, receptors for advanced glycation end products; HLA-DR, human
leukocyte antigen-DR; CECAM-1, carcinoembryonic antigen-related cellular adhesion molecule -1; PHOX, phagocytosis associated oxidase; CD, Crohn's disease; IBD, inammatory
bowel disease; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; PAF, platelet activating factor; MDSCs, myeloid-derived
suppressor cells.
Corresponding author. Department of Pediatrics, Faculty of Medicine, Sainte-Justine Hospital, University of Montreal, Montreal H3T1C5, Canada.
E-mail address: vij_tox@yahoo.com (V. Kumar).

1567-5769/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.intimp.2010.08.012
1326 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334
very important innate immune cells comprising the rst line of innate
immunity [1]. They were rst discovered by Elie Metchnikoff in
starsh larvae as a consequence of inammatory immune response
against inserted rose thorns. Thus, since their discovery, neutrophils
are considered as potent inammatory cells causing inammatory
tissue damage. However, neutrophils are not the only cells involved in
inammation. They act as rst innate immune cells which migrate to
the site of infection or inammation for containment and clearance of
infectious particles. Besides this, they also provide signals to other
innate immune cells about an invading foreign threat. For this
function, they must be considered as innate immune system's elegant
shooters against invading pathogens. Instead, they are viewed as rude
and unrened legionnaires, whose successful tasks are often associ-
ated with collateral tissue damage [2]. Till now, more attention has
been paid towards understanding the phagocytic uptake, intracellular
degradation of infectious agent, extracellular discharge of antimicro-
bial peptides and acute inammatory response of neutrophils towards
invading microbes. Recent advances made in understanding the
immunobiology of innate immune system have changed the scenario
of neutrophil biology, including their properties and function. In this
present review, an attempt is made to highlight the role of neutrophils
in innate immune system activation and function, its interaction with
various innate immune cells (i.e. macrophages, DCs) and adaptive
immune system (T cells and B cells).
2. Neutrophils in acute bacterial infections and inammation
Neutrophils or polymorphonuclear lymphocytes (PMNLs) are
essential innate immune cells which determine the host's resistance
against various bacterial and fungal infections. For example, persons
with severe neutropenia or chronic granulomatous disease (CGD) are
frequent sufferers of a wide range of microbial infections [3,4]. In
patients with peripheral blood counts b500 granulocytes/ml, clinical
morbidity from infections rises effectively and these patients
experience 43 episodes of severe infections for every approximately
3 years observed [5]. Thus, neutrophils are important innate immune
cells, which protect hosts from invading pathogens by using different
defense strategies.
3. Antimicrobial activity of neutrophils in acute infections
To serve as potent innate immune cells against pathogenic
microbes, neutrophils are laden with various cytotoxic granules
enriched with different powerful antimicrobial molecules (i.e.
cationic peptides, proteases, lactoferrin and myeloperoxidase, etc.).
However, on the basis of presence or absence of myeloperoxidase
(MPO), these granules can further be categorized as peroxidase
positive granules (also known as primary or azurophilic granules) [6]
or peroxidase negative granules (i.e. called specic or secondary
granules) [7]. With regard to their function, neutrophils can be
classied on the basis of their matrix contents or their integral
membrane proteins [8]. Peroxidase negative granules are most
relevant to integral membrane proteins as the membrane surround-
ing them expresses functionally diverse numbers of integral proteins
[i.e. 2 integrins, nicotinamide adenine dinucleotide phosphate
(NADPH), oxidase component avocytochrome b558, formyl peptide
receptors, fusogenic proteins called SCAMP (secretory carrier mem-
brane protein), vesicle-associated membrane protein-2 (VAMP-2), a
fusogenic protein, and urokinase type plasminogen-activating recep-
tor (uPAR)] [914]. However, the phenomenon of exocytosis from
neutrophilic granules is very interesting. Granules which are formed
at earlier stages of neutrophil maturation exhibit very little capability
of exocytosis during infection or inammatory process (i.e. azur-
ophilic granules are formed during promyelocytic stage, specic
granules are formed during myelocytic stage) [1416]. While granules
which are formed later in neutrophil maturation stages for example,
gelatinase granules (formed at metamyelocyte stage) and secretory
vesicles (formed by endocytosis) exhibit the phenomenon of
exocytosis most readily [1618]. However, the tendency to exocytose
depends on the density of expression of VAMP-2. That is why
secretory vesicles express the highest level of VAMP-2 as compared to
gelatinase granules or specic granules [19]. This explains that upon
stimulation with different stimuli (i.e. increased intracellular Ca2+
concentration or inammatory stimulus like microbes) neutrophil
exocytosis occurs in a random manner. Granules expressing the
highest levels of v-SNARE (i.e. VAMP-2) exocytose rst from
neutrophils upon activation [16]. This phenomenon shows that how
neutrophils make rm contact with activated endothelium, release
high concentration of gelatinase or metalloproteinase 9 (MMP9) and
express leukolysin (MMP25) on its surface, while passing through the
basement membrane without releasing tissue-destructive serine
proteases (cathepsin G, neutrophil elastases and proteinase 3)
[16,20]. These serine proteases remain bound to the neutrophil
surface when azurophilic granules fuse with plasma membrane
during this process [16,20].
Azurophilic granules of neutrophils are rich in various serine
proteases (i.e. cathepsin G, neutrophil elastases, proteinase 3 and
azurocidin) and play an important role in pathogenesis of acute
infections and inammation. For example, mice which are decient in
cathepsin G are more susceptible to Gram-positive bacterial infections
(i.e. infections caused by Staphylococcus aureus) [21]. Mice decient in
neutrophil elastases are more prone to develop Gram-negative
bacterial infections including Escherichia coli, Klebsiella pneumoniae
and many enterobacterial infections [22,23]. Papillon-Lefevre syn-
drome (PLS) is a rare genetic disease occurring due to loss of function
mutations in genes encoding an enzyme called dipeptidyl peptidase I
(DPPI) or cathepsin C. This enzyme is required for conversion of
inactive zymogen form of serine proteases to their active form.
Neutrophils isolated from these patients lack active serine proteases
and are also decient in this enzyme [24]. However, neutrophils of
these patients are not uniformly defective in their microbicidal
activity against common pathogens and exhibit normal antimicrobial
activity against E. coli and S. aureus. This explains why only a small
percentage of these patients is susceptible to severe systemic
infections.
4. Neutrophil extracellular traps (NETs) in immunity and infection
In addition to exhibiting phagocytic activity against pathogenic
bacteria and releasing antimicrobial molecules, neutrophils also form
neutrophil extracellular traps (NETs) to regulate severity of infection
[25]. NETs are formed as a consequence of extracellular release of
neutrophil nuclear contents. NETs are composed of decondensed
chromatin material and some granular (i.e. serine proteases) as well
as cytoplasmic proteins [26]. These NETs are capable of binding to
both Gram-negative as well as Gram-positive bacteria. NETs can easily
degrade bacterial virulence factors and kill bacteria extracellularly
due to their high serine protease content [26]. NETs have also been
seen in vivo in experimental model of dysentery and human
appendicitis samples [26]. In various vertebrate species including
humans, mice, chickens and zebra sh, NETs play an important role in
containment of infection and inammation [2729]. NETs can bind
and kill various microorganism including S. aureus, Shigella exeneri,
Streptococcus pyogenes, Bacillus anthracis, Mycobacterium tuberculosis,
fungus, Candida albicans, and parasites like Leishmania amazonensis
[3035].
Till now, two models of NETs released in extracellular space from
neutrophils have been described: (a) one involves the release of NETs
from dying neutrophils, thus involving the cell death mechanism and
the second involves (b) extrusion of chromatin material along with
serine proteases from intact neutrophils. The rst mechanism of NET
formation from neutrophils occurs within 23 hours of exposure to
 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334
phorbol myristate (PMA), S. aureus, or C. albicans as stimuli. The
second process of NET formation involves recognition of lipopolysac-
charide (LPS) or pathogenic bacteria by platelets or neutrophils. This
second process of NET formation occurs very rapidly leading to NET
formation within minutes upon exposure to stimuli. However, this
second process of NET formation is linked with vascular obstruction
observed during sepsis. During severe sepsis, platelets via toll-like
receptor 4 (TLR-4) act as a barometer for systemic infection. Platelets
bind avidly to sequestered neutrophils, leading to NET formation
within minutes. This traps bacteria present in the systemic circulation
but this also causes endothelial cell damage and hepatic damage [36].
The molecular mechanism of NET formation is unclear and it is
believed that reactive oxygen species (ROS) plays a central role. This is
because neutrophils isolated from patients suffering from chronic
granulomatous disease (CGD) are not capable of forming an effective
NET [30,33,37]. Neutrophils of CGD patients are unable to kill
Aspergillus nudilans in vitro but gene therapy in these patients
restored NET formation and resulted in recovery from Aspergillosis
[38,39]. Thus, NET formation by neutrophils helps in the containment
of infection along with decreasing inammation by releasing anti-
inammatory lipoxins and lowering pathogen load [25]. Additionally,
uptake of apoptotic neutrophil material (i.e. NETs) by macrophages
leads to the release of resolvins and protectins, which further inhibit
neutrophil recruitment [40].
5. Neutrophil and macrophage interaction
Neutrophils are the rst line of innate immune defense against
acute infections. However, signals which report acute inammation or
infection also cause the activation of other innate immune cells like,
epithelial cells, mast cells, macrophages, endothelial cells and
platelets, etc. Due to their common origin, neutrophils and macro-
phages share several functions in common (i.e. phagocytosis of
invading pathogens, similar kinetic behavior during infections or
inammation and their antimicrobial as well as immunomodulatory
properties) [41]. However, neutrophils make an important contribu-
tion in the activation and recruitment of macrophages at the site of
infection or acute inammation. Upon their activation, they generate
various chemotactic factors which attract monocytes/macrophages
and dendritic cells (DCs) [42,43] (Fig. 1). For example, activated
neutrophils release macrophage inammatory protein-1 (MIP-1)
and MIP-1 [44,45]. To a large extent, MIP-1 and MIP-1 show
overlapping biological activities. Along with activating monocytes and
macrophages, they also activate NK cells and immature DCs [4648]
(Fig. 1). Another study showed that stimulation of neutrophils with
outer membrane vesicle (OMV) from serogroup B Neisseria meningit-
ides led to the production of TNF-, IL-8, MIP-1 and MIP1- [49].
This study further indicates that activated neutrophils, by releasing
various chemokines, activate and recruit monocytes/macrophages at
the site of inammation. Thus, neutrophils may inuence the
phenomenon of macrophage differentiation into proinammatory or
anti-inammatory subtype [42,50]. Release of interferon- from
activated neutrophils causes activation of macrophages [51] (Fig. 1).
Besides releasing various pro-inammatory cytokines, neutrophils
also secrete myeloperoxidase (MPO) [52]. However, upon its release
from neutrophils, the enzyme becomes inactive very frequently in
tissue microenvironment. Therefore, both enzymatically active MPO
and enzymatically inactive MPO (iMPO) are present at inammatory
sites [5355]. MPO has a direct effect on tissue damage but it is also
taken up by residential macrophages expressing macrophage man-
nose receptors (MMRs) [56]. MPO and MMR interaction leads to
release of reactive oxygen species (ROS) along with other pro-
inammatory cytokines (i.e. TNF-, IL-1, IL-6, IL-8 and GM-CSF) from
macrophages [5761] (Fig. 1). Thus, binding of MPO with MMR
receptors in inammatory environment [i.e. inammatory joints of
patients of rheumatoid arthritis (RA) or acute infectious inammatory
1327
conditions like, acute lung injury or acute respiratory distress
syndrome (ARDS) observed during pneumonia] stimulates macro-
phages to release pro-inammatory molecules [62,63]. Therefore,
inhibition of this interaction can help in downregulation of inam-
matory tissue damage (Fig. 1). Macrophages by releasing TNF-, IL-
1, G-CSF and GM-CSF at the site of inammation or infection increase
survival of recruited neutrophils (i.e. the short life span of resting
neutrophils 612 h increases to 2448 h) [6467] (Fig. 1). This data
shows that neutrophils and macrophages at the site of infection act in
cooperation and help each other to work effectively.
Interleukin-17 (IL-17) cytokine is mainly associated with chronic
infectious diseases or autoimmune diseases [68] but also plays an
important role as rst line of defense against infections as a part
of innate immune system [6972]. It is mainly secreted by T cells,
CD4+TH17 and NK T cells [7274]. However, neutrophils also release
this cytokine [75,76]. IL-17 acts on neutrophils indirectly by
increasing their number through G-CSF [74]. Thus, neutrophils by
releasing IL-17 increase their survival, number and recruitment at
the site of infection [70,77,78] (Fig. 1). But IL-17 released by
neutrophils along with their recruitment also attracts macrophages
[78]. Neutrophils also release IL-8 and growth-related gene product-
representing their stereotyped response during recognition of foreign
particle or ligand [79]. IL-8 and growth-related gene product- in turn
acts as a chemoattractant for them and have redundant effect on
neutrophils [79].
Neutrophil activation during acute infection or inammation leads
to synthesis and release of various chemokines which act as potent
activators of monocytes/macrophages. Once these macrophages are
activated, they prolong neutrophil life span at the site of inammation
or infection by releasing IL-1, TNF-, G-CSF, and GM-CSF [64,66,67].
Clustering of neutrophils and macrophages is reported in various
infectious diseases like mycobacteriosis, oral and systemic listeriosis,
salmonellosis and legionellosis, etc. [8086]. In these infections,
neutrophils increase the antimicrobial action of macrophages by
providing potent antimicrobial molecules for which macrophages are
decient [80,8789].
6. Neutrophil and dendritic cell (DC) interaction
Dendritic cells (DCs) are potent antigen presenting cells (APCs)
and are involved in the activation of T cell immune response against
invading pathogens [90]. However, studies have shown neutrophil
and DC interaction during various infectious conditions [91]. Neu-
trophils act as transport vehicle for intracellular pathogens and
deliver antigens to DCs, and thus play an important role in activation
of T-cell immune response by DCs [9294]. Mice subjected to
neutropenia at an early stage of Legionella pneumophila infection
showed loss of Th1 immune response [95].
Upon activation by various inammatory stimuli like formyl-
methionyl-leucyl-phenylalanine (fMLP), C5a, platelet activating fac-
tor (PAF), lipopolysaccharide (LPS), and TNF-, neutrophil granules
release several inammatory proteins with the potential to induce
maturation of immature DCs [16,96] (Fig. 2). These protein molecules
also include alarmins [i.e. defensins, cathelicidins (LL-37), eosinophil-
associated ribonucleases (e.g. eosinophil-derived neurotoxin), high-
mobility group proteins (e.g. high-mobility group box-1 (HMG-B1),
granulysin and iron-binding proteins (i.e. lactoferrin), which are
released as a consequence of rst host innate immune response to
infectious or inammatory agents and lead to activation of both
innate as well as adaptive immunity [9799] (Fig. 2). Alarmins induce
the maturation of immature DCs and their recruitment at the site of
inammation by acting on Gi-protein-coupled-receptor (GiPCR)
and activating receptors or also by stimulating the production of
chemokines from leukocytes [96]. Somehow, defensins also
stimulate maturation of immature DCs by binding to TLR-4 receptors
expressed on immature DCs and induce antigen-specic adaptive
1328 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334

Infection or
Inflammation

Increase in neutrophil survival

Increased neutrophil
survival
through through G-CSF
G-CSF PMN P
MI -1 and MIP-
Activati
on Macrophages, NK Cells and

immature DCs activation

IL-17 Increased Neutrophil Survival

MPO Blockade

TNF- MMR Interaction

IL-8 IFN-

Macrophages Activation and

attraction at the recruitment of Macrophage Activation
site of infection Macrophages
or inflammation

Release of ROS (i.e. O2., H2O2),

and TNF-, IL-1, IL-6, IL-8 and
GM-CSF

Fig. 1. Activation and interaction of neutrophils with macrophages at the site of infection or inammation. MIP-1 and MIP-1 activate monocytes, macrophages, NK cells and
immature DCs. IFN- released from neutrophils also causes activation of macrophages. MPO released from neutrophils binds to MMR expressed on macrophages leads to activation
of pro-inammatory function of macrophages, which in turn increases neutrophil survival. IL-17 released by neutrophils increases their survival through G-CSF (for details see text).

immunity [100]. -Defensins, human neutrophil peptide-1 and -2
(HNP-1 and -2) secreted by human neutrophils exhibit chemotactic
properties for T cells and immature DCs only [101].
LL-37, a cathelicidins in humans and mouse cathelin-related
antimicrobial peptide (mCRAMP) in mouse, encourage both activa-
tion as well as differentiation of monocyte-derived DCs [102104].
Cathelicidin-mediated differentiation of monocytes into DCs
involves the activation of mitogen-activated protein kinase
(MAPK) pathway in vitro [102,105]. Cathelicidins in the presence
of self DNA potentially activate plasmacytoid DCs, increase the
expression of co-stimulatory molecules, type-1 interferon synthesis
and exacerbate autoimmune diseases like psoriasis by stimulating
TLR-9 [106]. However, a recent study has shown that cathelicidins
have the potential to block DC TLR-4 activation and may inhibit
allergic contact dermatitis [107]. Based on these observations, it
remains to elucidate the exact role of cathelicidins in DC stimulation
and maturation. Lactoferrin at higher concentrations (10100 g/
ml) effectively stimulates monocyte-derived DCs and peripheral
blood DCs [108,109]. This action of lactoferrin on DCs can stimulate
adaptive immune response and may be responsible for the anti-
tumor effect of lactoferrin [110112]. The stimulatory effect of
lactoferrin on DCs may be TLR-4-dependent as their activation is
inhibited when TLR-4 is absent (i.e. DCs from C3H/HeJ mice) or is
blocked by anti-TLR-4 antibodies [113]. HMG-B1is another alarmin
 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334 1329

Infection or

Inflammation

TNF- f-MLP C5a PAF LPS

Stimulation and Activation of

Neutrophils
Release of TNF-

Maturation of DCs IL-12

Release of Alarmins (i.e. Defensins, LL-3, HMG-B1, Granulysin or Lactoferrin etc.)

Activation of APCs i.e. macrophages or DCs

Immature DCs Act on GiPCR and

Activating Receptors (ARs) on DCs

Maturation of DCs Recruitment of DCs at the site of infection or inflammation

Release of IL-12
Activationof Th1immune
response

Fig. 2. Role of neutrophil alarmins in induction of maturation of immature DCs (iDCs) and their migration at the site of infection or inammation. Upon activation, neutrophils secrete
different alarmins (i.e. defensisns, LL-37, HMG-B1, etc.), which activate macrophages and DCs. Activation of DCs leads to activation of T cell immune response by directly acting as an
antigen-presenting cell or by releasing IL-12 (for details see text).

which induces the migration and activation of DCs leading to
polarization of Th1 immune response [114116]. This effect of
HMG-B1 is mediated by its binding to different receptors including
receptors for advanced glycation end products (RAGE), TLR-2, TLR-4
and TLR-9 [117119]. Thus, neutrophil alarmins play an important
role in interaction between neutrophils and DCs.
Along with production of alarmins, neutrophils also release certain
chemokines, which attract immature DCs at the site of infection or
inammation to clear pathogen or antigen [91]. TNF- released by
activated neutrophils plays an important role in the maturation of DCs
[120]. Besides these chemical interactions, physical interaction between
neutrophils and DCs also occurs. During physical interaction, neutro-
phils interact with DCs via glycosylation-dependent interactions
between Mac-1 and DC-SIGN leading to the delivery of activation
signals and antigenic molecules to DCs [93,121]. Neutrophil binding to
immature DCs causes their maturation leading to expression of co-
stimulatory molecules [i.e. CD80, CD86, CD40 and human
leukocyte antigen-DR (HLA-DR)] [122]. In addition to Mac-1, CECAM-
1 (carcinoembryonic antigen-related cellular adhesion molecule -1 or
CD66a) expressed by neutrophils is also capable of binding to DC-SIGN
of DCs and regulates neutrophil proliferation and delays their apoptosis
[123125].
Recent ndings have shown that neutrophils undergoing apopto-
sis during normal physiological conditions are incapable of inducing
the maturation of immature DCs while neutrophils laden with M.
tuberculosis induced their maturation [126]. This maturation of DCs
was dependent on Mac-1 and DC-SIGN interaction and functional
endocytosis via v5. While soluble factors released during this
condition by neutrophils or blocking of CD36 were not able to induce
maturation of DCs [126]. For example, neutrophils infected with M.
tuberculosis release heat shock protein 72 (Hsp72) [127], but this Hsp
was not able to induce DC maturation when immature DCs were
treated with Hsp72 alone [126].
7. Neutrophils as inducers of adaptive immunity
Adaptive immune response comprises of activation of T cell and B
cell immune response against pathogenic organisms (i.e. bacteria,
viruses, fungi or parasites). However, earlier views in immunology
suggested that neutrophils are key players in the innate immune
1330 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334
system, which has an important role in phagocytosizing bacteria and
release of antimicrobial molecules. While, T cells are more frequently
involved in defense against viral infections, anti-tumor immune
response or pathogenesis of autoimmune diseases. Now this scenario
is changing and evidences are increasing continuously for the
activation of T cells in bacterial infections, co-localization of both
neutrophils and T cells at the site of persistent or chronic bacterial
infections or chronic inammatory conditions like cancers. For
example, in patients suffering from implant-associated osteomyelitis,
major inammatory cell population comprises of neutrophils (50
70%) but the second largest cell population is of T cells (up to 70%)
[128]. Besides that, PMNs can also contribute to the development of
delayed type hypersensitivity (DTH) by releasing monocyte chemo-
tactic protein-1(MCP-1)/CCL2 and transition from innate to adaptive
immune response [65,129]. Serine protease called cathepsin G
secreted from neutrophils has a tendency to bind lymphocytes and
modulate antigen-specic humoral immune response in mice [130
132]. Co-administration of cathepsin G in mice along with antigens
caused signicant increase in production of antibody against that
antigen along with a signicant increase in IFN- production and
induction of synthesis of antigen-specic IL-4 [20]. Thus, neutrophil
serine proteases have a potent adjuvant activity and can be used as
future neoadjuvants in vaccine design.
Neutrophils, by inducing maturation of immature DCs and
increasing expression of co-stimulatory molecules (HLA-DR, CD86,
CD46, etc.), provide signals for induction of T cell immune response.
Interaction of neutrophils with DCs induces production of interleukin-
12 (IL-12) by DCs and helps in their maturation and activation of T
cells [93,133] (Fig. 2). This is because mature DCs have capability to
polarize T cells and to differentiate T cells into Th1, Th2 immune T
cells. For example, DCs cultured with neutrophils are capable of
inducing Th1 immune response primarily [123] (Fig. 2). This same
situation is found in the inamed intestinal mucosa of Crohn's disease
patients, where both neutrophils and DCs are located in close
proximity and inammation is mainly due to the activation of Th1
immune response [134]. Thus, neutrophil interaction with DCs may be
responsible for the induction of Th1 immune response and generation
of exaggerated inammatory tissue damage [121,123].
Along with activating DCs to stimulate T cell immune response,
neutrophils also act as antigen-presenting cells because neutrophils
express MHC class II molecules when they are present as bystander
cells in monocyte T-cell antigen presentation assay or when cultured
in the presence of GM-CSF, IL-3, IFN- [135,136]. Thus, neutrophils
primed with histiocytes or other immune cells (i.e. monocytes or
macrophages) are capable of acting as antigen-presenting cells
(APCs). However, the extent of MHC class II expression on PMNs
varies and can act as a factor in different groups of people susceptible
to different autoimmune or other immunological inammatory
conditions (i.e. antibody production to PMNs cytoplasmic contents)
[137]. Neutrophils cultured in the presence of autologous serum, IFN-
and GM-CSF expresses high level of MHC class II, CD80 and CD86
molecules [138]. This makes them efcient APCs, which are capable of
inducing strong T cell immune response against antigen in a MHC
class IIrestricted manner [138]. Neutrophils also take care of
extracellular bacteria as well as other particulate antigens through
an alternative MHC class I antigen processing pathway by presenting
antigens to cytotoxic T cells [92]. This alternative antigen-processing
pathway exhibited by neutrophils can be inhibited by cytochalasin D,
while remaining unaffected by lactacystin (a proteasome inhibitor) or
brefeldin A (a blocker of anterograde transport from endoplasmic
reticulum to Golgi apparatus) [139]. Besides expressing MHC class I
and II molecules, human peripheral blood neutrophils also express
other accessory molecules called B7-1 like molecule constitutively
which interacts with CD28 expressed on T cells [140]. This interaction
between CD28 and B7-1 augments IFN- secretion by T cells [141].
Thus, expression of these co-stimulatory effector molecules by
neutrophils and their interaction with corresponding ligands
expressed on T cells may impart different effector functions to these
T cells during infectious or other inammatory disorders [91,142].
8. Neutrophils and Th17 cells cross-talk
Th17 cells are novel subsets of CD4+ effector T helper (Th) cells,
which produce IL-17A (also called IL-17) as a major cytokine along
with IL-17F, IL-21, IL-22, IL-26 and CCL20 [143,144]. Th17 cells play an
important role in the pathogenesis of chronic inammatory diseases
like psoriasis, Crohn's disease (CD), and allergic asthma, and CCR6-
expressing Th17 cells inltrating the inamed joints of rheumatoid
arthritis (RA) patients has also been observed [145,146]. Thus, the
study of regulation of function and mobilization of these Th17 cells by
neutrophils may play an important role in studying the pathogenesis
of these chronic inammatory disorders. Recently, Pelletier et al. have
shown that neutrophils stimulated with a combination of IFN- and
LPS produce CCL20, CCL2 and CXCL10, which exhibit a signicant
chemotactic effect on Th17 and Th1 cells. These Th17 cells expressed
higher levels of IL-23R and IL-17 mRNA [147]. However, this
chemotactic effect was not observed for Th2 clones of T cells [147]
because neutrophils do not produce classic Th2-recruiting chemo-
kines CCL17 and CCL2 [147]. Th17 cells indirectly recruit and activate
neutrophils through IL-17-induced induction of CXCL8, CXCL1 and G-
CSF by epithelial cells and other stromal cells [148]. However, a recent
study has shown that Th17-mediated chemotactic effect on neutro-
phils is mainly through CXCL8 [147]. Pelletier et al. have also shown
that IL-17A and IL-17F do not have a direct effect on gene expression
of CCL20, CCL2, CXCL10 and CXCL8 in human neutrophils [147]. This
observation was made on the nding that human neutrophils express
only IL-17RA but not IL-17RC subunit required for the normal function
of multimeric receptor for IL-17A and IL-17F [147]. Neutrophils can
also play an important role in Borellia burgdorferi NapA-driven Th17
cell inammation in Lyme arthritis by releasing IL-23 [149].
In a murine model of Legionella pneumophilainduced pneumonia,
early recruitment of neutrophils contributes to Th1 polarization [150]
and induces resistance to Trypanosoma cruzi infection in BALB/c mice
by altering the Th1/Th2 cytokine response towards Th1 immunity
[151]. Thus, neutrophils preferentially recruit and modulate the
functions of Th17 and Th1 cells, but not of Th2 cells. Neutrophils
and Th17 cell also co-localize in gut tissues isolated from CD patients
and synovial uid from RA patients [147], asthma [152], gastric
Helicobacter pylori infection [153], in an experimental model of
inammatory bowel disease (IBD) [154] and in animal model of
experimental autoimmune encephalitis (EAE) induced by adoptive
transfer of Th17-polarized myelin-reactive T cells [155]. Thus,
neutrophils play an important role in regulating Th1, Th17 immune
response in various inammatory conditions and the study of
interaction between these cells will provide newer approach to
design effective immunotherapeutics for treating these inammatory
diseases.
9. Myeloid-derived suppressor cells (MDSCs) and suppression of T
cell immune function
Myeloid-derived suppressor cells (MDSCs) were rst character-
ized in humans suffering from cancer and in mice bearing tumors
[156]. Their number increases up to 10-fold in humans affected with
different kinds of cancers [157160]. In humans, these are character-
ized by the presence of CD14CD11b+ cells or cells expressing CD33
but not markers of mature myeloid and lymphoid cells along with
MHC class II molecule HLA-DR [157,158]. An increased number of
MDSCs in the tumor environment induces an immunosuppressive
condition by inhibiting T cell immune response providing favorable
conditions for tumors to grow and metastasize. Earlier studies have
shown that direct cell to cell contact is necessary for their immune-
 V. Kumar, A. Sharma / International Immunopharmacology 10 (2010) 13251334
suppressive action [156]. For example, MDSCs express high levels of
arginase 1 and inducible nitric oxide synthase (iNOS), both arginine
and nitric oxide (NO) play an important role in T cell immune
response [161,162]. Increased activity of arginase 1 in MDSCs leads to
depletion of arginine from tumor microenvironment and causes
suppression T cell immune response by different mechanisms,
including decreased expression of CD3 chain [163], downregulating
the expression of cyclin D3 and cyclin-dependent kinase 4 (cdk4)
[164]. While NO generated by MDSCs suppresses T cell immune
response by inhibiting Janus-associated kinase 3 (JAK3) and signal
transducer and activator of transcription 5 (STAT5) pathways in T
cells [165], by inducing their apoptosis [166] and by inhibiting MHC
class II expression [167]. Besides that, upon reacting with superoxide
anion, NO forms a more reactive species called peroxynitrite, which
causes nitration and nitrosylation of the amino acids cysteine,
tyrosine, methionine, and tryptophan [168]. In human prostate
carcinoma, high levels of nitrotyrosine in T cells due to the action of
peroxynitrite, makes them unresponsive to tumor antigen [169].
Direct contact of T cells with MDSCs leads to the nitration of T cell
receptor (TCR) and CD8 molecules making them unresponsive to
specic antigen stimuli [170,171]. Also, interaction of MDSCs with NK
cells leads to the release of IL-13, which inhibits CD8 T cell immune
response [172,173].
MDSCs promote de novo development of forkhead box P3 (FOXP3)
regulatory T (Treg) cells in vivo and regulate immunosuppressive
environment in tumor microenvironment [174176]. However, this
induction of Treg cells by MDSCs requires differential activation of
tumor-specic T cells and the presence of IFN- and IL-10 [175].
However, some studies showed that this phenomenon also required
cytotoxic lymphocyte antigen 4 (CTLA 4) by MDSCs [174], arginase 1
but not TGF- [177]. However, there are also some studies which
show that MDSC co-expressing CD80 and CD86 have a limited role in
the induction of Treg cell expansion and MDSCs are not involved in Treg
cell induction [178,179]. Thus, further studies are required for
determining the exact role of MDSCs in the induction of Treg cell
mediated immunosuppression.
Besides activating T cell immune response, neutrophils can also
suppress T cellmediated immune activation by releasing reactive
oxygen species (ROS) (O.2, H2O2 etc.) and nitrogen intermediates (NO
etc.) [180,181]. This is because neutrophils are rich in enzymes [i.e.
nitric oxide synthase (NOS) and phagocytosis-associated oxidases
(PHOX)] which play an important role in the generation of ROS and
nitrogen intermediates [182]. In various solid tumors, these activated
neutrophils (or also called low-density granulocytes) downregulate
CD3 chain expression and inhibit cytokine production by T cells via
H2O2 production [182,183]. Thus, neutrophils and MDSCs during
infection and other inammatory disorders (i.e. cancer, autoimmune
diseases) play an important role in the regulation of T cell immune
response depending on the stage of their activation.
10. Future perspective
Earlier, to immunologists, pathologists, rheumatologists or oncol-
ogists, neutrophils were kind of innate immune cells which were
responsible for tissue damage or inammation. Their activation was
always considered detrimental to the host. However, now the
scenario is changing. Today, we know that persons or experimental
animals decient in neutrophils are more prone to develop bacterial
or fungal infection as compared to their normal counterparts. Also in
mouse models of cancer and in certain tumors in humans, neutrophils
showed anti-tumor effect [184,185]. Clinical trials had also been
conducted where complement-xing, neutrophil-recruiting tumor-
specic monoclonal antibodies were administered to patients with
end stage metastatic melanoma [186]. However, further studies are
also required for the use of neutrophil-mediated anti-tumor therapy.
In addition to this, neutrophils are emerging as innate immune cells,
1331
whose activation links both innate immunity and adaptive immunity.
For example, neutrophils, macrophages, DCs and T cells co-localize at
various infectious (i.e. M. tuberculosis) or inammatory sites, where
neutrophils act as rst innate immune cells and provide signals for the
activation of other innate immune cells (i.e. macrophages and DCs)
and T cells.
Thus, earlier concepts of activation of innate immune response
and adaptive response separately should be considered outdated.
Yamazaki and Aoki (1998) have shown that neutrophil cathepsin G
has the potential to increase NK cellmediated cytotoxicity in a
dose-dependent manner [187]. A recent study has shown that
neutrophil and macrophage interaction during acute infection or
inammation leads to the production of a peptide called, innate
defense regulator 1 (IDR1), which shows the same activity as
defensins or cathelicidins LL-37 [188]. This peptide activates
antimicrobial activity of macrophages [189]. Thus, a healthy
partnership between neutrophils and macrophages plays a very
important role in the onset and resolution of inammation [189].
Hence, understanding of neutrophil interaction with macrophages
may open doors for designing better molecules to control
overwhelming inammatory tissue damage.
Along with the activation of innate or adaptive immune cells,
neutrophils by releasing arginase or ROS may deactivate natural killer
(NK) cell or T cell activation by depleting the extracellular L-arginine
levels required for T cell activation [180,190,191]. Hence, neutrophil
activation is not only involved in the activation of innate or adaptive
immune response but also suppresses overwhelming function of both
arms of the immune system. A recent study by Greenblatt et al. has
shown that calcineurin signaling plays an important role in regulation
of antifungal immune response by neutrophils [192]. Their nding
supports that disseminated fungal infections observed in patients
treated with immunosuppressive drugs like cyclosporine or FK506 are
not just due to suppression of adaptive immunity only but occur due
to suppression of neutrophils mediated innate immune response
against fungal antigens [192]. However, further future detailed studies
at the molecular levels will add in the mechanisms involved in the
regulation of NK cells or T cell function by neutrophils in vivo. Thus,
neutrophils have the ability to prime both innate and adaptive arms of
immune system depending on their stage of activation and are the
Cinderellas of the innate immune system.
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