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The inflammasome in pathogen recognition and inflammation

Fayyaz S. Sutterwala,*,† Yasunori Ogura,† and Richard A. Flavell†,‡,1


Sections of *Infectious Diseases and †Immunobiology and the ‡Howard Hughes Medical Institute, Yale University
School of Medicine, New Haven, Connecticut, USA

Abstract: The nucleotide-binding oligomerization The plant NBS-LRR-type R proteins have evolved diver-
domain-like receptor (NLR) family of proteins is gently to protect the host from various pathogens, and some
involved in the regulation of innate immune re- NBS-LRR-type R proteins have been demonstrated to bind
sponses and cell death pathways. Some NLR family pathogen-derived molecules [6, 7]. However, it remains un-
members promote the activation of proinflam- clear whether the NBS-LRR-type R proteins are direct patho-
matory caspases within multiprotein complexes, gen recognition receptors or sensors of cellular distress. For
called inflammasomes. Recent studies analyzing example, a NBS-LRR protein of Arabidopsis, RPS5, recognizes
mice deficient in various components of the inflam- a fragment of the host protein PBS1, which is generated by the
masome have provided insight into the role of these protease activity of the Pseudomonas syringae protein AvrPphB
molecules in host defense against pathogens and in following its injection into host cells by the bacteria [8]. This
autoinflammatory disorders. Here, we review these finding implies that this NBS-LRR protein recognizes a con-
studies and propose that membrane disruption sequence of the activity of pathogens rather than the presence
leads to activation of the inflammasome. J. Leukoc. of the pathogen itself.
Biol. 82: 259 –264; 2007.

Key Words: innate immunity 䡠 NLR 䡠 NALP3 䡠 IPAF 䡠 caspase-1 THE INFLAMMASOME: A MOLECULAR
PLATFORM TO ACTIVATE CASPASE-1

INTRODUCTION Although caspases are known to play an essential role in


apoptotic cell death, a member of the caspase family,
The mammalian nucleotide-binding oligomerization domain caspase-1, regulates the secretion of the proinflammatory cy-
(NOD)-like receptor (NLR) family of intracellular proteins is tokines IL-1␤ and IL-18 by cleaving the corresponding, im-
characterized by a unique nucleotide-binding domain called mature proforms of these cytokines, pro-IL-1␤ and pro-IL-18.
NACHT—found in neuronal apoptosis inhibitory protein IL-33, a cytokine involved in generation of TH2 responses, is
(NAIP), Class II transactivator (CIITA), incompatibility locus also processed by caspase-1 [9]. Besides caspase-1, four more
protein from Podospora anserina (HET-E), and telomerase- caspases, which are phylogenetically related to caspase-1, are
associated protein (TP-1)—which is located at the center of the also implicated in the regulation of inflammation and therefore,
molecule between an N-terminal protein-binding caspase-re- called inflammatory caspases. These are caspase-1, caspase-4,
cruitment domain (CARD), pyrin domain (PYD), or baculovirus and caspase-5 in humans and caspase-1, caspase-11, and
inhibitor of apoptosis repeat (BIR) and a C-terminal leucine- caspase-12 in the mouse [10]. Although human and mouse
rich repeat (LRR) domain [1– 4] (Fig. 1). The NLR family caspase-1 are orthologs, human caspase-4 and caspase-5 are
members Nod3, Nod4, and Nod5 contain an as-of-yet unde- likely to have arisen from gene duplication of caspase-11 [10].
fined domain at their N terminus. The structure of NLR pro- In contrast to murine caspase-12, human caspase-12 appears
teins resembles that of Apaf-1 of vertebrates and insects, to be inactive [11].
Ced-4 of C. elegans, and the nucleotide-binding site (NBS)- Based on analogy to the induced-proximity model for the
LRR-type disease-resistance proteins (R proteins) of plants, all activation of the apoptotic caspases 8 and 9 by CD95/Fas-
of which contain another type of nucleotide-binding domain, death-inducing signaling complex (DISC) and the Apaf-1-ap-
NB-ARC or apoptotic ATPase, which is also centrally located optosome, respectively, a putative, molecular platform to acti-
between an N-terminal protein-binding domain (CARD, TIR, vate the inflammatory caspases has been termed the “inflam-
or CC domain) and a C-terminal WD40 or LRR domain [5]. masome” [12–14]. Tschopp and colleagues [12, 13] proposed
Our understanding of the mechanism of NLR molecules is an inflammasome model based on biochemical analysis of three
based on evolutionary similarities with other innate immune
receptors, which contain a LRR motif (i.e., TLRs and plant
NBS-LRR-type R proteins); NLR molecules are postulated to
1
function as intracellular pathogen recognition molecules. The Correspondence: Section of Immunobiology, Yale University School of
Medicine, 300 Cedar Street, TAC S-569, New Haven, CT 06520, USA. E-mail:
NACHT domain regulates activity of the molecule in a way that
richard.flavell@yale.edu
is dependent on ligand binding to the LRR motif, and the Received December 22, 2006; revised April 3, 2007; accepted April 5,
N-terminal protein-binding domain then transmits a signal to 2007.
specific downstream effectors. doi: 10.1189/jlb.1206755

0741-5400/07/0082-259 © Society for Leukocyte Biology Journal of Leukocyte Biology Volume 82, August 2007 259
adaptors bind to caspase-1 through CARD-CARD interactions
so that a complex composed of a single NALP3, ASC, and
Cardinal molecule can attract two caspase-1 molecules to this
caspase-1 activation platform, the NALP3 inflammasome.
There is no Cardinal homologue in the mouse, and hence,
murine NALP3 is thought to recruit only a single caspase-1
molecule (Fig. 2). NALP1 and NALP2 also have been shown
to form similar caspase-1-activating platforms. It remains un-
clear whether the NALP3 inflammasome is stably present in
the cytoplasm or if it is assembled by upstream signals as in the
apoptosome or DISC.
Another NLR protein, IPAF [also known as CARD12 or
caspase-associated recruitment domain, LRR, and NAIP-,
CIIA-, HET-E-, and TP1-containing protein (CLAN)], can bind
to and activate caspase-1 through its N-terminal CARD [15]
and may form a homo-oligomeric complex—the IPAF inflam-
masome. Three other PYD-containing NLR proteins, NALP6
(Pypaf-5), NALP12 (Pypaf-7 or Monarch-1), and NALP10
(Pynod), and another PYD-containing protein, Pyrin (MEFV),
have also been reported to modulate caspase-1 activity through
an ASC-mediated pathway [16 –19]. Depending on the activat-
ing stimulus, the composition of the inflammasome can be
quite varied, and multiple, different types of inflammasome
Fig. 1. Domain structure of the NLR protein family. NAD, NACHT-associ- may exist.
ated domain; FIIND, domain with function to find; IPAF, IL-1␤-converting
enzyme protease-activating factor; AD, activation domain; APAF1, apoptosis
protease activating factor-1; NB-ARC, nucleotide-binding-adaptor shared by
APAF-1, R proteins, and Caenorhabditis elegans cell death gene 4 (CED-4) NALP3 AND DANGER SIGNALS
domain; WD-40, Trp-Asp 40; A. thaliana RPP5 and RPS2, Arabidopsis thali-
ana genes RPP5 and RPS2, respectively; TIR, Toll/IL-1 receptor homologous
region; CC, coiled-coil; Cys, cysteine-rich domain; TM, transmembrane do-
Macrophages secrete IL-1␤ in response to serial stimulation
main; ASC, apoptosis-associated speck-like protein containing a CARD do- with LPS followed by ATP. In this experimental system, LPS or
main. ATP alone are not sufficient to induce IL-1␤ secretion, and
LPS is required to induce pro-IL-1␤ and to prime cells for
caspase-1 activation in response to ATP [20]. The stimulation
NLR proteins, NALP1, NALP2, and NALP3. NALP3 (also of cells by high concentrations of ATP is thought to mimic the
known as cryopyrin, CIAS-1, Pypaf-1, or CLR1.1), which has a rapid release of ATP from activated platelets, neurons, antigen-
PYD at its N terminus, binds to two kinds of adaptor proteins, stimulated T cells, and injured cells. The effect of ATP is
ASC and a CARD-containing protein (Cardinal); both of these mediated by the P2X7 receptor, which causes a rapid K⫹ efflux

Fig. 2. Activation of the NALP3 inflamma-


some by microbes, toxins, and danger signals.
The pathogens Listeria monocytogenes and
Staphylococcus aureus, microbial toxins (mai-
totoxin, aerolysin, and nigericin), and danger
signals (ATP and uric acid) have all been
implicated in the activation of the NALP3
inflammasome. A number of these stimuli me-
diate a potassium efflux; however, it is still
unclear if NALP3 inflammasome activation by
uric acid and S. aureus is dependent on po-
tassium. These stimuli likely lead to a confor-
mational change in NALP3 by an unknown
mechanism, which allows NALP3 to oligomer-
ize. Following oligomerization, NALP3 re-
cruits ASC through a homophilic PYD-PYD
interaction. ASC, in turn, recruits pro-
caspase-1 via homophilic CARD-CARD in-
teractions, which lead to activation of
caspase-1, and active caspase-1 can then pro-
cess pro-IL-1␤ and pro-IL-18 and induce
macrophage cell death. LLO, Listeriolysin-O;
P2X7, an ionotropic ATP receptor.

260 Journal of Leukocyte Biology Volume 82, August 2007 http://www.jleukbio.org


from the cytosol upon activation [21, 22]. As potassium iono- NALP3-dependent activation of caspase-1 (Y. Ogura and R. A.
phores, membrane-permeablizing agents, pore-forming agents, Flavell, unpublished observations). These data suggest that the
and K⫹ depletion from cell culture media are also known to pore-forming capacity of LLO on the plasma membrane of the
induce IL-1␤ secretion, the efflux of cytosolic potassium is macrophage results in a potassium efflux, which in turn leads
thought to be an essential trigger of caspase-1 activation [23– to the activation of the NALP3 inflammasome. Unlike LLO-
27]. Recent studies have identified pannexin-1, a membrane deficient L. monocytogenes, S. aureus singly deficient in ␣-, ␤-,
protein that can act as a nonselective pore, as being required or ␥-hemolysin were still capable of activating caspase-1 [31].
for caspase-1 activation in response to ATP, nigericin, and This may be a result of redundant membrane disruptive toxins
maitotoxin. Pannexin-1 is thought to act downstream of the K⫹ still present when only a single hemolysin is absent.
efflux and may play an important role in the activation of the The pore-forming toxin aerolysin from Aeromonas hydrophila
NALP3 inflammasome [28, 29]. is also able to activate caspase-1 by mediating a potassium
Studies using macrophages from NALP3-deficient mice have efflux [33]. Using small interfering RNA to silence expression
shown that NALP3 plays a central role in caspase-1 activation of NALP3, ASC, or IPAF in HeLa cells, the NALP3 and IPAF
in response to TLR stimulation combined with potassium efflux inflammasomes were implicated in mediating caspase-1 acti-
(Fig. 2). NALP3-deficient macrophages stimulated with TLR vation in response to aerolysin [33]. It will be informative to
agonists plus ATP, nigericin, or maitotoxin failed to secrete determine the roles of NALP3 and IPAF in aerolysin-mediated
IL-1␤ and IL-18 [30 –32]. This defect in IL-1␤ and IL-18 caspase-1 activation using primary cells from NALP3- and
secretion was found to occur at the level of caspase-1 activa- IPAF-deficient mice.
tion, as stimulation of NALP3-deficient macrophages with LPS Kanneganti et al. [34, 35] have suggested that NALP3 and
plus ATP did not result in the autocatalytic cleavage of pro- ASC are essential for caspase-1 activation in response specif-
caspase-1 into its p20 and p10 subunits. In vivo, mice chal- ically to bacterial RNA, the imidazoquinoline compounds
lenged with LPS showed increased resistance to endotoxic R837 and R848, and viral dsRNA. Their studies found that
shock in the absence of ASC or NALP3 [30, 31]. ASC-deficient these PAMPs were capable of activating caspase-1 in the
mice, however, tolerated higher doses of LPS compared with absence of ATP, which is in contrast to the findings of others.
NALP3-deficient mice, suggesting that ASC, being a common In addition, this study failed to observe ATP-mediated
downstream adaptor for multiple NLR molecules, may play caspase-1 activation in response to other TLR ligands such as
additional roles in endotoxic shock, which do not overlap with LPS, lipoteichoic acid, and Pam3CSK4. The reason for the
those of NALP3. discrepancy between this study [34] and the others [30 –32]
In a separate study, Martinon and colleagues [32] dem- remains unclear.
onstrated that monosodium urate (MSU) and calcium pyro-
phosphate dihydrate (CPPD) crystals activate caspase-1 in a
NALP3-dependent manner. Deposition of MSU and CPPD BACTERIAL ACTIVATION OF THE IPAF
crystals in joints is responsible for the inflammatory condi- INFLAMMASOME
tions gout and pseudogout, respectively. It is unclear if MSU
and CPPD activation of the NALP3 inflammasome is depen- Caspase-1 is important for host defense to a number of patho-
dent on K⫹ effluxes, similar to other NALP3 inflammasome- gens. Infection of macrophages with Salmonella, Shigella, Le-
activating agents such as ATP and nigericin. This study gionella, and Pseudomonas all lead to caspase-1 activation,
identifies NALP3 as playing a potentially important role in release of IL-1␤, and rapid cell death. The caspase-1-mediated
inflammatory joint disease. In addition to its role in gout, cell death caused by infection with Salmonella typhimurium
uric acid is a major component released into the extracel- was found to be independent of NALP3 [30, 31]. S. typhi-
lular milieu by necrotic cells. Recognition of uric acid murium-infected macrophages did, however, require IPAF to
following cell death may be an additional way in which activate caspase-1 [36] (Fig. 3). Recent studies in our lab
NALP3 detects endogenous danger signals. suggest that P. aeruginosa-induced activation of caspase-1 is
also dependent on IPAF (F. S. Sutterwala and R. A. Flavell,
unpublished observations). The role for ASC in IPAF-mediated
BACTERIAL ACTIVATION OF THE NALP3 caspase-1 activation is unclear. Although IPAF can interact
INFLAMMASOME directly with procaspase-1, ASC-deficient macrophages have
delayed kinetics of cell death following infection with S. typhi-
Secretion of IL-1␤ and IL-18 by macrophages in response to murium compared with wild-type. This suggests ASC may
infection with S. aureus and L. monocytogenes is dependent on serve a role stabilizing the interaction between IPAF and
ASC and NALP3 [31] (Fig. 2). Mutant L. monocytogenes defi- procaspase-1.
cient in LLO were unable to induce caspase-1 activation in Despite the dramatic in vitro effects of IPAF deficiency on S.
wild-type macrophages, suggesting that LLO-mediated escape typhimurium-induced macrophage death, IPAF-deficient mice
of L. monocytogenes from the phagosome into the cytosol was infected orally with S. typhimurium did not display enhanced
crucial for activation of the NALP3 inflammasome, presumably susceptibility to infection [37]. However, caspase-1-deficient
by allowing the detection of pathogen-associated molecular mice infected with S. typhimurium were more susceptible to
patterns (PAMPs) now released into the cytosol. We however infection, as demonstrated by a shorter time until death and
found that LLO-containing supernatants, in the absence of higher bacterial burdens in spleen and mesenteric lymph
bacteria, added to macrophages extracellularly, result in the nodes. The in vivo difference seen between caspase-1-deficient

Sutterwala et al. The inflammasome 261


Fig. 3. Activation of the IPAF inflamma-
some by Type III and Type IV secretion sys-
tems. Activation of caspase-1 following infec-
tion of macrophages with S. typhimurium,
Pseudomonas aeruginosa, or Legionella pneu-
mophila requires a functional Type III or Type
IV secretion system. Infection causes IPAF to
undergo a conformational change by an un-
known mechanism, which allows IPAF to oli-
gomerize. Following oligomerization, IPAF re-
cruits procaspase-1 via homophilic CARD-
CARD interactions, which lead to activation
of caspase-1. Bacterial-derived cytosolic
flagellin likely enhances or in the case of L.
pneumophila, is required for the activation
of the IPAF inflammasome through a possi-
ble interaction with Naip5. Activation of
caspase-1 following infection by Francisella
tularensis requires the adaptor molecule
ASC and likely activates an inflammasome
through an unknown NLR molecule. Dis-
ruption of the phagosome by F. tularensis is
required for activation of caspase-1.

mice and IPAF-deficient mice may be a result of additional, IPAF detects membrane damage induced by Type III or Type
undefined pathways, which result in caspase-1 activation, or a IV secretion systems. Flagellin may serve to enhance Type III
synergistic effect among IPAF, NALP3, and ASC. or Type IV secretion system-dependent caspase-1 activation
L. pneumophila can also mediate macrophage cell death through aiding bacterial adhesion to the host cell. Alterna-
through a caspase-1-dependent manner [38] (Fig. 3). The ac- tively, flagellin may interact with Naip5, which in turn associ-
tivation of caspase-1 by L. pneumophila is dependent on IPAF ates with IPAF.
but not NALP3 [38, 39]. L. pneumophila is unique in that
another NLR member, Naip5 (Birc1e), is also involved in
susceptibility to infection with L. pneumophila [40, 41]. These
findings link Naip5 to the caspase-1 pathway, which is sup- MEMBRANE DISRUPTION AS A POSSIBLE
ported by the observation that Naip5 and IPAF can interact TRIGGER FOR INFLAMMASOME ACTIVATION
physically [38].
Recent studies have begun to provide insight into how the Mariathasan and colleagues [49] have recently shown that F.
IPAF inflammasome is activated. S. typhimurium [42, 43] and tularensis is also capable of mediating macrophage cell death
L. pneumophila [44, 45] strains deficient in flagellin were found in a manner that is dependent on ASC and caspase-1, and
to be defective in their ability to activate caspase-1. Purified caspase-1- and ASC-deficient mice infected in vivo with F.
flagellin delivered to the macrophage cytosol by transfection tularensis showed increased susceptibility to infection com-
was also capable of activating caspase-1 [42, 43]. These find- pared with wild-type mice. NALP3 and IPAF were not found to
ings led to the hypothesis that cytosolic flagellin contributes to be responsible for mediating caspase-1 activation in response
the activation of caspase-1. However, the direct activation of to infection with F. tularensis, suggesting another NLR family
IPAF by cytosolic flagellin remains controversial for several member plays a role in the detection of F. tularensis. It is
reasons. First, the P. aeruginosa mutant PAK⌬fliC, which is interesting that F. tularensis mutants, which could not escape
deficient in flagellin, is still capable of activating caspase-1 in from the phagosome, did not induce caspase-1 activity [49].
an IPAF-dependent manner (F. S. Sutterwala and R. A. Fla- This suggests that disruption of the phagosome membrane may
vell, unpublished observations). Second, the nonflagellated be yet another signal to activate a specific NLR pathway.
bacterium Shigella flexneri has also been suggested to activate Caspase-1 has also been found to play a role in membrane
caspase-1 in an IPAF-dependent manner [46]. Finally, Miao et repair. Gurcel et al. [33] found that aerolysin-induced mem-
al. [43] showed that at a high multiplicity of infection, flagellin- brane disruption leads to a K⫹ efflux, which is responsible for
deficient S. typhimurium strains were still capable of inducing activation of NALP3 and IPAF inflammasomes [33].
macrophage secretion of IL-1␤. Caspase-1, which is activated in this manner, induces the
A common feature that S. typhimurium, S. flexneri, and P. activation of sterol regulatory element-binding proteins, which
aeruginosa share is their requirement for an intact, Type III promote cell survival through membrane repair [33]. It is
secretion system (TTSS) to activate caspase-1 [47, 48]. L. unclear why activation of caspase-1 in response to pathogens
pneumophila-induced caspase-1 is dependent on the Dot-Icm such as Salmonella, Shigella, and Pseudomonas leads to cell
Type IV secretion system, which is unrelated structurally but death, whereas caspase-1 activation by aerolysin toxin leads to
similar functionally to the TTSS [38]. As flagellin alone is not increased cell survival. Specific activation of caspase-1 via
sufficient to activate the IPAF inflammasome, it is possible that NALP3 or IPAF inflammasomes may be responsible for guid-
rather than detecting a specific pathogen-derived molecule, ing this process.

262 Journal of Leukocyte Biology Volume 82, August 2007 http://www.jleukbio.org


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ACKNOWLEDGMENTS J., Fernandes-Alnemri, T., Alnemri, E. S. (2006) Cryopyrin and pyrin
activate caspase-1, but not NF-␬B, via ASC oligomerization. Cell Death
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264 Journal of Leukocyte Biology Volume 82, August 2007 http://www.jleukbio.org