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Abstract | Inflammatory and apoptotic caspases are central players in inflammation and
apoptosis, respectively. However, recent studies have revealed that these caspases have functions
beyond their established roles. In addition to mediating cleavage of the inflammasomeassociated cytokines interleukin1 (IL1) and IL18, inflammatory caspases modulate distinct
forms of programmed cell death and coordinate cell-autonomous immunity and other
fundamental cellular processes. Certain apoptotic caspases assemble structurally diverse and
dynamic complexes that direct inflammasome and interferon responses to fine-tune
inflammation. In this Review, we discuss the expanding and interconnected roles of caspases
thathighlight new aspects of this family of cysteine proteases in innate immunity.
Inflammasomes
Multi-protein complexes
that activate caspase 1
toinduce processing of
pro-interleukin1 and
prointerleukin18 and to
drive pyroptosis.
Pyroptosis
An inflammatory and lytic
formof programmed cell
deathmediated by
inflammatory caspases.
Apoptosis
A non-inflammatory form
ofprogrammed cell death
mediated by apoptotic
caspases. Apoptotic cells
exhibit membrane blebbing
(but have an intact cell
membrane), DNA
fragmentation and
cellshrinkage.
Department of Immunology,
St Jude Childrens Research
Hospital, Memphis, Tennessee
38105, USA.
Correspondence to T.-D.K.
thirumala-devi.kanneganti@
stjude.org
doi:10.1038/nri.2015.7
Published online 14 Dec 2015
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Table 1 | Classification of caspases
Caspase
Classification
Initiator or
effector
Genomic location
Domain structure
Human
Mouse
Caspase 1
Inflammatory
Initiator
11q23
9 A1
Caspase 2
Apoptotic
Initiator
7q347q35
6 B2.1
Caspase 3
Apoptotic
Effector
4q34
8 B1.1
Caspase domain
Caspase
domain
| Immunology
DEDNature
DED Reviews
Caspase
domain
Caspase 4
Inflammatory
Initiator
11q22.211q22.3
Absent
Caspase 5
Inflammatory
Initiator
11q22.211q22.3
Absent
Caspase 6
Apoptotic
Effector
4q25
3 H1
CARD Reviews
Caspase
domain
| Immunology
DEDNature
DED
Caspase
domain
| Immunology
DEDNature
DED Reviews
Caspase
domain
Caspase domain
domain
CARD
Caspase
CARD
Caspase domain
DED DED
Caspase domain
Caspase domain
Caspase
domain
Nature
| Immunology
CARD Reviews
Caspase
domain
Caspase 7
Apoptotic
Effector
10q25
19 D2
Caspase 8
Apoptotic
Initiator
2q332q34
1B
Caspase 9
Apoptotic
Initiator
1p36.21
4 E1
Caspase 10
Apoptotic
Initiator
2q332q34
Absent
Caspase 11
Inflammatory
Initiator
Absent
9 A1
Initiator
11q22.3
9 A1
Caspase 14
Effector
19p13.1
10 C1
Death receptors
A subset of receptors within
the tumour necrosis factor
receptor superfamily that, on
binding to their ligands, convey
cell death signals.
Keratinocyte
differentiation
CARD
DED DED
DED DED
CARD
CARD
Caspase domain
Caspase domain
Caspase domain
Caspase domain
domain
Caspase
Caspase domain
Caspase
domain
Nature Reviews
| Immunology
Nature Reviews | Immunology
DED
Caspase domain
domain
DED DED
DED
Caspase
Nature Reviews | Immunology
CARD
CARD
Caspase
Caspase domain
domain
DED DED
DED
DED
Caspase
Caspase domain
domain
Caspase domain
domain
Caspase
CARD
Caspase
domain
CARD Reviews
Caspase
domain
|| Immunology
Nature
Immunology
DEDNature
DED Reviews
Caspase
domain
DED DED
Caspase domain
Caspase
domain
Caspase domain
domain
CARD
Caspase
CARD
Caspase domain
Caspase
domain
Nature Reviews
Reviews
Immunology
Caspase
domain
Nature
|| Immunology
CARD, caspase activation and recruitment domain; DED, death effector domain. *The human genome encodes 12 caspases. Two
Nature
Reviews
| Immunology
isoforms of human caspase 12 have been identified. Caspase 12S is an inactive truncated isoform (not
shown),
whereas
caspase
Nature
Reviews
| Immunology
12L is an active full-length isoform.
Apoptosome
A multi-protein complex
comprised of apoptotic
protease-activating factor 1
(APAF1) and caspase 9, which
induces the intrinsic pathway
of apoptosis.
Microorganism-associated
molecular patterns
(MAMPs). Conserved
structures that constitute
microorganisms (for example,
lipopolysaccharide or flagellin),
which are recognized by
pattern-recognition receptors.
Damage-associated
molecular patterns
(DAMPs). Molecules that are
released by injured cells (for
example, ATP or host DNA)
and are recognized by
pattern-recognition receptors.
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Box 1 | Discovery of caspase 1 and inflammasomes
Caspase 1 was identified in 1989 and named interleukin1 (IL-1)converting enzyme (ICE) owing to its ability to convert
the 31 kDa proIL1 into an active 17.5 kDa fragment182,183. Characterization of purified caspase 1 in 1992 revealed that it
is a heterodimeric cysteine protease composed of two subunits, p10 and p20 (REF.184). Caspase 1 mediates proteolytic
processing of IL18 with similar efficiency185. In 2002, the existence of a macromolecular protein complex comprised of
caspase 1, caspase 5, an adaptor protein known as apoptosis-associated speck-like protein containing a CARD (ASC) and
NOD-, LRR- and pyrin domain-containing protein 1 (NLRP1) was described in an overexpression and cell free system21.
This elegant study provided evidence that caspase 1 is activated in a large
multi-protein complex initiated by a member of the NOD, LRR-containing
protein (NLR) family. The term inflammasome was then coined to describe
its multi-protein composition. In 2004, mutant mouse strains were
generated with a genomic deletion of ASC and NOD-, LRR- and
CARD-containing protein 4 (NLRC4); macrophages from these mice failed
to engage caspase 1 activation and did not process proIL1 in response to
infection by the intracellular bacteria Salmonella enterica subsp. enterica
serovar Typhimurium140, thereby providing the first line of genetic evidence
for the role of an NLR in the modulation of inflammasome activities under
endogenous settings. In addition, three groups independently showed in
2006 that another member of the NLR family, NLRP3, assembles the
inflammasome to activate caspase 1 in response to ATP, bacterial RNA
molecules and uric acid crystals141143. The absent in melanoma 2 (AIM2)
andpyrin inflammasomes were subsequently identified in later
studies146149,186,187. Inflammasomes can be visualized as a distinct speck
byfluorescence or confocal microscopy95,111,144,145,188 (see figure; arrows
indicate ASCcaspase 1 inflammasomes in macrophages transfected with
double-stranded DNA. Scale bar represents 10m).
Nature Reviews | Immunology
Alarmin
A damage-associated
molecular pattern that is
released by damaged or
necrotic cells in response to
infection or injury. Alarmins
arerecognized by pattern-
recognition receptors to
furtheractivate immune cells.
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a
B. anthracis
S. Typhimurium
F. novicida
Protective
antigen
T3SS
ATP, pore-forming
toxins, ion ux and
particulate matters
Vacuole
Toxin-induced
modications
of RHO GTPases
IRF1
Needle Inner rod Flagellin
Lethal factor
CMV or
e
vaccinia virus
GBPs
CARD
ASC
dsDNA
NAIP6
NAIP5
NAIP2
NAIP
LRR
NAIP1
Caspase 11independent
(canonical)
NLRP1B
Pyrin
AIM2
NLRP1B
PYD
NLRC4
NLRP3
Pro-caspase 1
NLRP1B inammasome
NLRP3 inammasome
NAIPNLRC4 inammasome
AIM2
inammasome
Pyrin
inammasome
Active caspase 1
Gasdermin D
N-terminal fragment
Pro-IL-1
IL-1
Pyroptosis
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Non-canonical NLRP3
inflammasome
An inflammasome containing
NLRP3 that is activated by
Gram-negative bacteria or
lipopolysaccharide, requiring
activation of caspase 4 or
caspase 5 in human cells
andcaspase 11 in mouse cells.
Canonical inflammasomes
Inflammasomes that do not
require caspase 4, caspase 5
and caspase 11 for their
activation, including the
canonical NLRP3, NLRC4
andAIM2 inflammasomes.
Guanylate-binding proteins
A group of interferon-inducible
GTPases produced by the
hostcell that often target
pathogen-containing vacuoles,
contributing to the release of
pathogens from the vacuole
and mediating pathogen killing.
contribute to the protection against colorectal tumorigenesis and subsequent growth of metastasized cancer
cells in mice6567. By contrast, activation of the NLRC4
inflammasome prevents cancer through a mechanism
that suppresses overt proliferation of colonic crypt
cells68. How NLRC4 and NLRP3 differentially coordinate caspase 1 functions to achieve IL18dependent
and -independent effects during colorectal tumori
genesis is largely unknown. Recent studies have also
demonstrated a requirement for caspase 11 in medi
ating resistance against dextran sulfate sodium-
induced intestinal inflammation in mice6971. Whether
IL1 and IL18 are contributing factors in this case is
contentious, with both similar and reduced levels of
IL1 and IL18 being reported in caspase 11deficient
micetreated with dextran sulfate sodium compared
with treated wild-type mice 70,71. Differences in gut
microbiota harboured by mice housed in different
facilities, together with differences in experimental conditions, could account for these discrepancies. Nevertheless, there is clear evidence to indicate
that caspase 1- and caspase 11mediated cellular and
pathological effects might occur independently of the
concomitant release of IL1 and IL18.
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Box 3 | Pyroptosis
The term pyroptosis was first proposed in 2001 to describe the pro-inflammatory and
caspase 1dependent nature of Salmonella-induced cell death and to distinguish it from
non-inflammatory apoptosis52. Pyro describes fire or fever and ptosis signifies a
pro-inflammatory form of programmed cell death. Pyroptosis is characterized by
rupture of the cell membrane and release of cellular contents, cell swelling, positivity
for annexin V and TUNEL staining, evidence of chromatin condensation and absence of
DNA laddering55,188. Furthermore, the mitochondria of pyroptotic cells lose membrane
potential and release their contents188. Several investigators have also referred to
caspase 11induced cell death as pyroptosis35,36,53,54. Caspase 11 activates pyroptosis in
response to Escherichia coli and other triggers of the non-canonical NOD-, LRR- and
pyrin domain-containing protein 3 (NLRP3) inflammasome29,33. It is important, however,
to note that caspase 11 induces cell death independently of caspase 1 and does not
directly cleave interleukin1 (IL1) and IL18. From this standpoint, it is likely that
caspase 1 and caspase 11dependent pyroptosis have their own set of molecular
signatures, some of which might be common. Both caspase 1 and caspase 11 cleave
a53kDa substrate known as gasdermin D, generating a 31kDa amino-terminal
fragment that initiates pyroptosis and a 22kDa carboxy-terminal fragment that has
unknown functions6264.
Necroptosis
A type of necrosis and a form
of non-apoptotic cell death
driven by the kinases RIPK1
and RIPK3 under conditions in
which caspase 8 is inhibited.
scores in AfricanAmericans with rheumatoid arthritis86. However, no association was found between a particular variant of caspase 12 and susceptibility to sepsis
induced by the fungal pathogen Candida albicans or to
community-acquired pneumonia87,88. There is also limited evidence to suggest that malaria contributed to the
persistence of caspase 12L in African populations89. The
reason for the apparent discrepancy between these studies is unclear. Nevertheless, it has been proposed that the
loss of caspase 12 function in many human populations
is indicative of a positive selection event that probably
occurred within the past 100,000years81. Consistent with
this idea, a loss of caspase 12 function in Europe has
been predicted to predate animal domestication and be
unrelated to zoonotic infections from livestock90.
Biochemical analyses have found that rat
caspase 12 cleaves itself and does not induce the
cleavage ofcaspase1, caspase 3, caspase 4, caspase 5,
caspase8, caspase 9, the apoptotic substrates polyADP-ribose polymerases (PARPs) and inhibitor of
caspase-activated DNase (ICAD; also known as DFFA),
proIL1, proIL18 or amyloid precursor proteins91.
However, the full-length or a catalytically inactive form
of rat caspase 12 interacts with caspase 1 and partially
withcaspase 5, but not with caspase 9 (REF.85), and
prevents caspase 1 activity and the release of IL1 in
macrophages stimulated with TLR ligands85,91. The
inhibitory activity of rodent caspase 12 does not seem
to be restricted to caspase 1. Overexpression of rat
caspase 12 in HEK293T cells dampens the activation
of nuclear factorB (NFB) signalling induced by
MDP92. Caspase12 displaces the E3 ubiquitin ligase
TNFR-associated factor 6 (TRAF6) in the NOD2
RIPK2 complex and interacts with the kinase RIPK2
(REF.92). The biochemical functions exhibited by rodent
caspase 12 raise the possibility that it might be an anti-
inflammatory caspase. However, further studies are
required to fully elucidate the immunological repertoire
of this understudiedcaspase.
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LPS
Gram-negative
bacteria
TLR4
TRIF
GBPs
Non-canonical
NLRP3 inammasome
LRR
Vacuole
LPS
NLRP3
PYD
Caspase 11
ASC
CARD
Pro-caspase 1
Active caspase 1
Gasdermin D
N-terminal fragment
Pro-IL-1
IL-1
Pyroptosis
REVIEWS
Direct cleavage of proIL1 by caspase 8 in macro
phages has been observed under conditions in which
inhibitor of apoptosis proteins (IAPs) are blocked. Genetic
deletion of X-linked IAP (XIAP; also known as BIRC4),
A. fumigatis
Candida spp.
M. leprae
Ligands
LPS
Yersinia spp.
Dectin 1
TLR
Classical
inammasome
activators
MDP
MYD88
Stress-induced
drugs
Poly(I:C)
TRIF
TLR3
NOD2
TRIF
NLRP3
Caspase 8
MALT1
BCL-10
RIPK3
PYD
Caspase 8
Mitochondrion
SMAC
IAPs
FADD
RIPK1
DED
Pro-apoptotic
stimuli
ER
ER stress
?
CARD9
LRR
FAS
TLR4
Endosome
SYK
FASL
FADD
ASC
FADD
FADD
CARD
Caspase 1
p50 p65
Caspase 1
inammasome
NF-B
Caspase 8
Caspase 8
Non-canonical
caspase 8 inammasome
Yersinia
spp.
Caspase 8
processing unit
Caspase 1
Caspase 1
processing unit
NLRP3
FAS
IL-1
Pro-IL-1
Pro-inammatory
cytokines
Nucleus
TNF
and IL-6
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Inhibitor of apoptosis
proteins
(IAPs). A family of proteins
thathave multiple functions,
including inhibition of
apoptosis by binding to
apoptotic caspases, E3
ubiquitin ligase activity,
regulation of MAPK and
NFBsignalling pathways
andregulation of signal
transduction by
pattern-recognition receptors.
REVIEWS
Precisely how caspase 1 and caspase 8 operate synergistically and independently of one another and the nature
of the activators that determine this relationship remain
to be fully elucidated. Interestingly, caspase 8dependent
activation of the NLRP3 inflammasome is regulated by
RIPK3 and the necroptosis effector mixed lineage kinase
domain-like (MLKL) only after prolonged stimulation157.
This would, in part, reflect the compositional flexibility
and dynamics of the caspase 8containing complex, which
is observed when different contextual cues are sensed by
the cell at different times. Moreover, the growing evidence
supporting a role for caspase 8 in the initiation of inflammation reinforces the perspective that the function of this
caspase is clearly not confined to apoptosis.
Inhibition of inflammation and the inflammasome. In
addition to its pro-inflammatory function, caspase8
has anti-inflammatory roles. Mice lacking caspase 8 in
hepatocytes or DCs develop chronic inflammatory or
autoimmune diseases158,159. Increased inflammation in
mice lacking caspase 8 in DCs could be prevented by deletion of the TLR adaptor MYD88, which suggests a role
for caspase 8 in supressing TLR signalling 159. In the skin,
loss of caspase 8 expression promotes IL1 secretion and
the transcriptional activation of NFBresponsive genes
during wound healing 160.
One of the abilities of caspase 8 to modulate inflammation includes inhibition of inflammasome activity
(FIG.4). The deficiency of caspase 8 in mouse DCs results
in assembly of the NLRP3 inflammasome and release of
IL1 in response to LPS or Pam3CSK4 even without an
inflammasome activator 120. LPS-induced IL1 production in DCs lacking caspase 8 requires RIPK1, RIPK3,
the effector MLKL and the serine/threonine protein
phosphatase PGAM5. This study suggested that LPS
stimulation of DCs promotes an association of caspase8
with FADD to inhibit the assembly of a RIPK1RIPK3
complex and its downstream effector functions, leading
to activation of the NLRP3 inflammasome120. It has also
been proposed that caspase 8 and FADD bind NLRP3
to directly inhibit the inflammasome120. It remains
unclear in what context caspase 8 functions as a negative
regulator of inflammation and whether this function is
cell-typespecific.
Inhibition of necroptosis. An indirect way in which
caspase 8 inhibits inflammatory responses is through its
ability to inhibit necroptosis an inflammatory form of
programmed cell death mediated by RIPK1 and RIPK3
independently of caspases20,123,124. In addition to its ability
to bind and inhibit RIPK1RIPK3mediated inflamma
some activation120, caspase 8 cleaves RIPK1, RIPK3 and
the deubiquitylating enzyme CYLD, which is responsible for removing ubiquitin chains from RIPK1 and
directing its function towards necroptosis161163 (FIG.4).
Indeed, spontaneous inflammation that develops in the
absence of caspase 8 is prevented by the inhibition of
necroptosis164,165. Mice with a conditional deletion of
the gene encoding caspase 8 in the intestinal epithelium
exhibit spontaneous ileitis, loss of Paneth cells and goblet cells, increased infiltration of granulocytes and CD4+
Tcells into the lamina propria, and increased expression of inflammatory markers164. Importantly, inhibition
of necroptosis by necrostatin1 largely prevents TNFinduced lethality and small intestinal tissue destruction
in these mice164. Another report also found that caspase8
prevents RIPK3mediated necroptosis, death of enterocytes and immune cell infiltration of the colon165. These
findings are further supported by a study showing that
mice lacking FADD in the intestinal epithelium are
hypersusceptible to necrosis of epithelial cells, loss of
Paneth cells and the development of colitis defects
that are largely prevented by genomic deletion of the
gene encoding RIPK3 (REF.166). The ability of caspase 8
to provide a checkpoint to suppress necroptosis-induced
inflammation adds another layer of functional complexity to this enigmatic protease.
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The intrinsic pathway of apoptosis regulated by
caspase 9 must also maintain immunological silence.
Released mitochondrial DNA owing to mitochondrial
outer membrane permeabilization activates the DNA
sensor cyclic GMPAMP synthase (cGAS) and its
adaptor stimulator of IFN genes (STING), which induce
typeI IFNs and IFN-stimulated genes for antiviral
Sendai virus,
VSV or poly(I:C)
Apoptotic
stimuli
TLR
Caspase 8
Intrinsic
apoptotic
pathway
Mitochondrion
BAX
RIG-I
ssRNA or
dsRNA
FADD
BAK
Cytochrome c
mtDNA
RIPK3
RIPK1
MLKL
PGAM5
Caspase 8
MAVS
RIPK1
Ub
Ub
Ub
Ub
Caspase 9
APAF1
DED
RIPK3
RIPK1
Cleaved RIPK3,
RIPK1 and CLYD
LRR
cGAS
Cleaved
RIPK1
WD40
Apoptosome
CYLD
NLRP3
PYD
Necroptosis
ASC
TBK1
P
IRF3 IRF3
CARD
P
STING
STING
Caspase 3
Caspase 7
Pro-caspase 1
NLRP3 inammasome
Pro-IL-1
Pyroptosis
IL-1
ER
P
IRF3 IRF3
Type I IFNs
and ISGs
Apoptosis
Nucleus
REVIEWS
Cell-autonomous immunity
A defence mechanism used by
the cell to control infection that
is not traditionally considered
as part of the immune system.
Examples include compartmentalization to prevent
inappropriate entry of bacteria
into the cytoplasm within a
eukaryotic cell and production
of nitric oxide synthases to
mediate killing of an invading
microorganism.
Conclusions
The caspase family members are architects of the body.
They maintain homeostasis by dismantling unwanted or
damaged cells in a systematic manner. Although caspases
are broadly classified into apoptotic and inflammatory
caspases, new and exciting studies are continuously
unveiling the multifaceted nature of individual caspases
in the immune system. Caspases function as pro-inflammatory and anti-inflammatory molecules, as well as having cell-intrinsic roles to orchestrate cell-autonomous
immunity. Converging roles of caspases in the immune
system are further exemplified by their ability to communicate with one another to maintain immunological
silence or to promote inflammatory responses to eliminate invading pathogens. Furthermore, the capacity
for inflammatory caspases to mediate sensing of LPS
signifies the importance of these proteases in pattern
recognition. These elegant and surprising findings
challenge the existing functional classification of the
caspase family members. The intertwining relationship
between caspases will be further defined in the future.
Understanding the expanding and interconnected
roles of caspases will contribute to the development of
therapies that target disease processes associated with
dysregulated caspaseactivity.
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Acknowledgements