And Sepsis the Host Response To

The Inflammatory Caspases: Key Players in the Host Response to Pathogenic Invasion and Sepsis

This information is current as Amal Nadiri, Melissa K. Wolinski and Maya Saleh of September 29, 2021. J Immunol 2006; 177:4239-4245; ; doi: 10.4049/jimmunol.177.7.4239 http://www.jimmunol.org/content/177/7/4239 Downloaded from

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BRIEF REVIEWS

The Inflammatory Caspases: Key Players in the Host Response to Pathogenic Invasion and Sepsis Amal Nadiri,1* Melissa K. Wolinski,1† and Maya Saleh2*

Caspases are cysteinyl-aspartate-specific proteinases lar partners and may therefore share common mechanisms of known for their role in apoptosis (cell death or apoptotic activation. The CARD domain contains a “death fold” struc- caspases) and proinflammatory cytokine maturation (in- ture also found in the death domain, death effector domain, flammatory caspases). The inflammatory caspases were and pyrin domain (PYD). The caspase catalytic region is com- among the first to be discovered, but only recently have the posed of both large and small subunits with a conserved mechanisms leading to their activation and inhibition be- QACXG active site sequence (where X is R, Q, or G) found in gun to be elucidated. In this review, we examine the bio- the large subunit (Fig. 1B). Caspases recognize a tetrapeptide Downloaded from motif in their substrates and have an absolute specificity for an chemistry, substrates, and function of this unique family aspartic acid residue at the scissile bond. The substrate specific- of inflammatory proteases, highlight the most recent find- ities for caspase-1, -4, -5, and -11 have been determined using ings regarding their regulatory mechanisms, and discuss small peptides in vitro, and were found to be similar with a pref- what remains to be understood about their roles in health erence for the sequence Trp-Glu-His-Asp (WEHD). However,

and disease. The Journal of Immunology, 2006, 177: caspase-12 seems to have acquired alterations in its catalytic http://www.jimmunol.org/ 4239–4245. function, as it only recognizes and cleaves itself in rodents (W. Shao and M. Saleh, manuscript in preparation) and appears inactive in humans (6). It is unclear whether the inflammatory aspases12 are essential proteases for the initiation and caspases play a direct role in apoptosis, as we lack mechanistic execution of apoptosis, and for the processing and information about both their execution of cell death and their maturation of the inflammatory cytokines IL-1␤ C cellular “apoptotic” substrates. In this study, we review the and IL-18 (1). In humans, the caspase family includes 13 mem- mechanisms regulating the inflammatory caspases, their func- bers that are classified into three groups according to their phy-

tion in inflammation and innate immunity, and what we have by guest on September 29, 2021 logenetic relationship (Fig. 1A), which seems to correlate with recently uncovered about their roles in both sepsis and the host functional relatedness (2). The cell death caspases are initiators immune response to pathogenic invasion. (caspase-2, -8, -9, and -10) and executioners (caspase-3, -6, and -7) of apoptosis. The initiator caspases sense death signals, and Gene orthology and chromosomal localization activate more downstream executioner caspases, which cleave The human inflammatory caspases include caspase-1 (IL-1␤- cellular substrates mediating the changes associated with apo- converting enzyme (ICE)), -4, -5, and -12. Mice have one fewer ptosis. However, this simplistic cascade is not the whole story, inflammatory caspase; caspase-5 is absent, probably having for “apoptotic” caspases, especially caspase-8, appear to have ad- arisen by tandem gene duplication of caspase-4 in higher spe- ditional functions unrelated to cell death. Caspase-8 has been cies. Mouse caspase-11 appears to be the ortholog of human shown to be required for T cell homeostasis, proliferation, and caspase-4. The genes for the inflammatory caspases cluster to- activation (3, 4), and for cell motility under nonapoptotic con- gether on human chromosome 11q22.2-q22.3 and on a syn- ditions (5). It remains to be determined whether other apopto- tenic region on mouse chromosome 9A1. They are arranged tic caspases, besides caspase-8, function in promoting cellular from telomere to centromere as caspase-1, -5, -4, and -12 in hu- survival. mans and as caspase-1, -11, and -12 in mice (Fig. 1C). Two Both inflammatory and apoptotic caspases are synthesized as demonstrated inhibitors of caspase-1, Iceberg and Cop or pseu- inactive zymogens and share a common conserved structure do-ICE, which are CARD-only proteins, are found in close composed of a prodomain and a catalytic region (Fig. 1B). The proximity to caspase-1 in the human but not the murine locus. prodomain contains a caspase-recruitment domain (CARD),3 The arrangement, proximity, as well as the exon-intron struc- which is also present in the cell death initiator caspase-2 and -9, ture of the inflammatory caspases, suggest that they originated suggesting that these caspases might interact with similar cellu- from the same ancestral gene(s).

*Department of Medicine, McGill University, Montreal, Canada; and †College of Osteo- 2 Address correspondence and reprint requests to Dr. Maya Saleh, Department of Medi- pathic Medicine, Michigan State University, East Lansing, MI 48824 cine, McGill University, Montreal, Quebec H3A 1A1, Canada. E-mail address: [email protected] Received for publication May 10, 2006. Accepted for publication June 28, 2006. 3 Abbreviations used in this paper: CARD, caspase-recruitment domain; PYD, pyrin do- The costs of publication of this article were defrayed in part by the payment of page charges. main; ICE, IL-1␤-converting enzyme; LRR, leucine-rich repeat; NLR, NOD-LRR; NAIP, This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. neuronal apoptosis inhibitor protein; NALP, Nacht, CRR, and PyD-containing protein; Section 1734 solely to indicate this fact. IPAF, ice protease activating factor; RIP, receptor-interacting protein; ER, endoplasmic 1 A.N. and M.K.W. contributed equally to this review. reticulum; Crm, cytokine response modifier; SNP, single nucleotide polymorphism.

FIGURE 2. Transcriptional splice variants of the human and mice inflam- Downloaded from matory caspases. Black boxes represent exons. Black lines represent introns. Dark red represents untranslated regions. The red asterisk denotes the position of the human caspase-12 SNP in exon 4.

Like caspase-1, mouse caspase-11 is expressed in the hemo- poietic and the CNS but found at low levels in most tissues. It is highly induced by LPS and IFN-␥ (18–21). In addition, it is http://www.jimmunol.org/ induced in the duodenum and jejunum following intestinal FIGURE 1. Phylogenetic relationship, domain organization, and chromosomal localization of the inflammatory caspases. A, Phylogenetic tree of the hu- mucositis, and in the brain following hypoxic and ischemic man caspase family. The inflammatory caspases are shown in red and the apo- brain injury (11, 22). ptosis caspases in black. B, The inflammatory caspases consist of a CARD or Caspase-12 is expressed in almost all tissues at the RNA level CARD-containing prodomain, and a large and a small catalytic subunit. For with the highest expression observed in the lung, stomach, and comparison, the CARD-only proteins COP, ICEBERG, and the caspase-12 small intestine (23, 24). Its constitutive protein expression, short variant are shown in gray. C, The human and mice inflammatory caspase however, is restricted to skeletal muscle, heart, brain, liver, loci on human chromosome 11q22 and mouse chromosome 9A1, respectively. eye, and testis. Its expression is low in the lymph nodes, thy- by guest on September 29, 2021 The genes are arranged from centromere to telomere with caspase-12 being ␥ closer to the telomere. mus, and spleen (25), but is highly inducible by IFN- and bacterial components in various cells including splenocytes and macrophages (24). Expression patterns and gene regulation The inflammatory caspases are held in check at different levels. Substrates Alternative splicing, tissue-specific distribution and gene induc- Very little is known about the physiologic substrates of the in- tion by inflammatory mediators add to the complexity of their flammatory caspases. Caspase-1 is known to cleave pro-IL-1␤ regulation. In total, there are 18 transcripts encoded by the hu- (26), pro-IL-18 (27), the related IL-1 family member IL-1F7b, man inflammatory caspases and 3 by their murine orthologs also known as IL-1H4 (28), and more recently IL-33 (29). It (Fig. 2). Alternative splicing of human caspase-1 yields five dif- has also been shown in vitro to process actin (30), the kinase ferent transcripts and that of human caspase-4 and -12 results in PITSLRE (31), and parkin (32). However, the relevance of this three and nine distinct transcripts, respectively. Human in the inflammatory response and programmed cell death re- caspase-5 as well as murine caspase-1, -11, and -12 each gener- mains unclear. Caspase-4 has been shown to process pro-IL-18 ate one transcript (7–12). and IL-1F7b inefficiently (28), and was suggested to cleave The expression patterns of the inflammatory caspases have caspase-3 into its active form (33). Caspase-5 was also reported been studied extensively. Caspase-1 and -5 share a similar pat- to cleave caspase-3 (34) and was shown to process the transcrip- tern of distribution. They are expressed at low levels in most tion factor Max in vitro (35). The only substrates known for tissues, but are constitutively expressed at high levels in mono- caspase-11 are caspase-1 (36) and -3 (37). Although it is clear cytes, macrophages, and to a lesser extent in neutrophils (13). that the inflammatory caspases, with the exception of caspase- Transcription from the caspase-5 gene is induced by LPS. In the 12, are catalytically efficient and can process multiple cellular nervous system, caspase-1 but not caspase-5, is found at higher proteins in vitro (S. Roy, J. R. Sharom, C. Houde, W. Shao, T. levels in neurodegenerative diseases such as Huntington’s and P. Loisel, J. P. Vallancourt, M. Saleh, and D. W. Nicholson, amyotrophic lateral sclerosis (14). Unlike caspase-1, caspase-5 unpublished observations), we still do not know of their in vivo is highly expressed in the heart and the colon. substrates. The finding that caspase-1 is secreted from macro- Caspase-4 differs from caspase-1 and -5 in that it is normally phages upon activation presents one possible explanation for present at high levels in most tissues. Its expression, however, is the lack of identified caspase-1 targets (38). Whether caspase-4, lower in the brain and colon than caspase-1 and -5, respectively. -5, and -11 are also secreted upon activation, and whether the One important characteristic of its gene regulation is its robust secretion of activated inflammatory caspases occurs in other tis- induction by IFN-␥ (15–17). sues such as neurons, which are reported to undergo apoptosis The Journal of Immunology 4241

“downstream” of the activation of caspase-1 and -11, remains to be determined.

Biological activities of the prime caspase-1 substrates IL-1␤ and IL-18 The role of caspase-1 in the maturation of IL-1␤ and IL-18 ren- ders it a key player in response to pathogenic infection as well as in inflammatory and autoimmune disorders. IL-1␤ and IL-18 are key cytokines in these conditions (39). Although they share certain proinflammatory activities, they also have very important individual functions. For example, IL-1␤ but not IL-18 is anorectic (40, 41), pyrogenic (42, 43), results in skin rashes and urticaria, induces hepatic-acute phase proteins (44, 45), up-regulates prostanoid synthesis, and is involved in inflammatory pain hypersensitivity (46). IL-1␤ is also implicated in destruc- tive joint and bone disease (47), tumor angiogenesis and invasiveness (48), and toxicity of insulin-producing pancreatic islets ␤ cells (49), and neurons in stroke and neurodegeneration (50).

IL-18, in contrast, was originally known for its ability to stim- Downloaded from ulate IFN-␥ production (51, 52) and to mediate T cell polar- ization. Now we know that it possesses many other functions including modulation of the heart contractile force (53), up- regulation of adhesion molecules and NO synthesis (54), and regulation of energy intake and insulin sensitivity (55). There- fore, inhibition of caspase-1 is an attractive therapeutic strategy http://www.jimmunol.org/ aimed at blocking the effects of both cytokines in inflammatory and autoimmune diseases. Although we know of many biological effects of IL-1␤ and IL-18, we still lack information on the exact mechanisms by which caspase-1 is activated, and by which these cytokines are matured and secreted.

Activators of the inflammatory caspases

Our knowledge about the mechanisms leading to caspase-1 ac- by guest on September 29, 2021 tivation has increased tremendously in the last few years. We knew for some time that bacterial products, ATP or Nigericin which alter the intracellular ionic milieu resulting in cytosolic acidification, lead to caspase-1 activation (56, 57). However, it was not clear how these signals converged on caspase activation. The characterization of the “inflammasome” as the macromo- lecular complex required for caspase-1 activation solved a big piece of the puzzle (38). The inflammasome resembles in many aspects the apoptosome, which is assembled during mitochon- drial apoptosis to activate caspase-9 (58). In both cases, the caspases are brought in close proximity in response to an activating signal via a scaffolding molecule. Apoptosis protease activating factor 1 is such a molecule in the apoptosome. Through its CARD domain it binds the CARD domain of caspase-9 and FIGURE 3. Caspase-1 activation pathways. In response to an inflammatory results in its activation in response to cytochrome c release from trigger or bacterial invasion (gray boxes), an NLR protein (NALP1, NALP3, the mitochondria. In the case of the inflammasome, members NAIP5, IPAF) oligomerizes and activates caspase-1 either directly or through an adaptor molecule (ASC, cardinal). The mechanism of caspase-1 activation is of the NOD-leucine-rich repeat (NLR) family act as regulators reminiscent of that of caspase-9 in the apoptosome. of caspase-1 activity (59) (Fig. 3). Although NOD1 and NOD2 activate the NF-␬B pathway upon sensing of pathogens (60, 61), NACHT, LLR, and PYD-containing protein (NALP)1, 2, chrome c is the stimulus activating the apoptosome, the ligand for 3 (38, 62), neuronal apoptosis inhibitor protein (NAIP) 5 (63), the inflammasome is unknown. Recently, multiple groups inves- and ice protease activating protein (IPAF) (64, 65) have all been tigating the NALP-3 inflammasome examined this question and shown to activate caspase-1. It is interesting to note that these showed that ATP, the toxin Nigericin (66), bacterial RNA (67), proteins share common structural determinants with apoptosis gout-associated monosodium urate, and calcium pyrophosphate protease activating factor 1, as they are able to recruit caspases dihydrate crystals (68) induce NALP-3 inflammasome activity. and oligomerize following the binding of nucleotides. The Similarly, Salmonella flagellin has been recently reported to activate questions that remain center around what ligand binds the scaf- the IPAF inflammasome (69, 70). It is unclear, despite this folding molecule to stimulate inflammasome assembly, and observed induction of the inflammasome, whether these stimuli what determines the specificity of that binding. Although cyto- interact directly with NALP-3 or IPAF. Moreover, one riddle 4242 BRIEF REVIEWS: THE INFLAMMATORY CASPASES remains: what determines which inflammasome is assembled in cytokine response modifier (CrmA) known to dampen the cy- response to a specific ligand? It is clear from both the NALP-3- tokine response (78). Using purified protein incubation tech- deficient mice (66–68) and from patients with the autoinflamma- niques and HPLC, CrmA was shown to inhibit caspase-1-me- tory disorders Muckle Wells syndrome, familial cold urticaria, and diated cleavage of pro-IL-1␤. This regulation of caspase-1 by chronic infantile neurologic cutaneous and articular syndrome CrmA was supported by later studies (as reviewed in Ref. 79). which are associated with NALP-3 mutations, that other NALPs Another proposed endogenous caspase-1 inhibitor is the pro- cannot compensate for the loss of NALP-3 (59). Similarly, teinase inhibitor, serpin PI-9. It is constitutively expressed NAIP-5, but not NALPs or NODs, is the specific molecule en- within human vascular smooth muscle cells, and was shown to gaged in response to Legionella pneumophila (63), indicating a high be responsible for caspase-1 inhibition and the resulting loss of degree of specificity in the inflammasome response and activation. pro-IL-1␤ and pro-IL-18 processing (80). In addition to CrmA The CARD-containing kinase receptor-interacting protein 2, and PI-9, caspase-1 enzymatic activity has been shown to be known for its function as a mediator of NOD2 signaling, was also inhibited by the CARD-only proteins ICEBERG and COP shown to function in the oligomerization and activation of (71, 81, 82). These proteins physically interact with caspase-1. caspase-1 (71, 72). We do not know, however, whether a “ligand” Therefore, it is conceivable that they inhibit caspase-1 by acting would directly activate RIP2 to induce its effects on caspase-1 or as dominant-negative regulators interfering with the recruit- whether NOD2 is involved in the RIP2-caspase-1 complex. In the ment of caspase-1 to an activating inflammasome. More re- mouse CNS, caspase-1 and -11 have been reported to be activated cently, we have shown that rodent caspase-12 also blocks by oxygen and glucose deprivation as well as following spinal cord caspase-1 catalysis as described in more detail below (24). Downloaded from injury (73, 74). Whether caspase activation in neurons is also mediated through an inflammasome remains to be determined. Interestingly, RIP2 appears to be the activator of caspase-1 in this Caspase-12 context (75). NOD2, in contrast, is suggested to assemble a A single nucleotide polymorphism (SNP) (T125GA 3 CGA) in caspase-1 inflammasome in the gut which is hyperactivated in exon 4 of the human caspase-12 gene results in the synthesis of

Crohn’s disease due to a mutation in its LRR (76). However, this either a truncated CARD-only protein or a full-length protein http://www.jimmunol.org/ awaits further characterization at the molecular level. (Fig. 1) (23). The majority of the human population has the The activation of caspase-4 and -5 has not been analyzed ex- premature stop codon at this position. However, in 20% of tensively in the studies mentioned above. In most instances, the people of African descent an arginine is present, resulting in activation of caspase-1 was assessed by determining the levels of read-through and synthesis of a full-length caspase-12 “proen- secreted IL-1␤ as a “read-out” and observation of caspase-1 pro- zyme” (6). We have previously shown that the presence of the cessing. The lack of “inflammatory” substrates for caspase-4 caspase-12 full-length variant dampened the inflammatory re- and -5 led researchers to examine the processing of these sponse of its carriers to endotoxins and was associated with se-

caspases as a read-out for activation. Caspase-5 was shown to be vere sepsis and sepsis-related mortality (6). A recent study ex- by guest on September 29, 2021 processed in the NALP-1 inflammasome (38), however, we do amining the age, geographical origin, and spread of the human not know whether the cleaved caspase-5 was active, and caspase-12 deleted form suggested that the stop codon arose in whether its was processed by caspase-1 or by a caspase-5 auto- Africa ϳ100,000 years ago (Fig. 4). This mutation was initially cleavage event. Consequently, we ignore whether the enzymatic neutral, but around 60,000 years ago, following the migration activity of caspase-5 is necessary in this context. The activation out of Africa, a positive selection force is believed to have driven of caspase-4 during inflammation has not been studied. In con- it to near fixation (83). The increase in population sizes and trast, caspase-4 has been reported to be activated by endoplas- densities in Europe and Asia and their exposure to rising infec- mic reticulum (ER) stress and to induce apoptosis in response to tious diseases and sepsis is believed to have constituted a selec- this stress as well as the neurotoxic peptide amyloid ␤, a fibril tive pressure favoring the truncated caspase-12 variant (83). associated with localized amyloidosis seen in Alzheimer’s dis- The positive selection advantage of the truncation of caspase-12 ease (17, 77). Caspase-4 was also reported to act downstream of is therefore proposed to be sepsis resistance. Fas ligation and to activate caspase-3 (33). In all other species sequenced to date, including rodents, and Old and New World primates, a coding amino acid exists at the Inhibitors of caspase-1 position equivalent to that of the human caspase-12 SNP, re- Our understanding of the regulation of the inflammatory sulting in the production of a full-length caspase-12 protein (6). caspases, especially caspase-1, has been fueled by several impor- In mice, caspase-12 was initially proposed to mediate ER-stress tant studies reporting on caspase-1 inhibitors. A first look at the induced apoptosis (84). However, we and others have shown inhibition of caspase-1 came from studies of the viral protein that caspase-12 deficient cells, in both humans and mice, are as

FIGURE 4. Geographical origin, date, and spread of the human caspase-12 polymorphism. The Journal of Immunology 4243

IL-18 production in human osteoarthritis cartilage explants (89). However, this compound was ineffective when adminis- tered orally. Other more specific caspase-1 inhibitors have been more recently described: 1) pralnacasan is an orally bioavailable pro-drug which, when metabolized, appears to be a selective, nonpeptidic inhibitor of caspase-1. In vitro, pralnacasan inhibited LPS-induced IL-1␤ and IL-18 release by human PBMCs (90, 91). In vivo, oral administration of pralnacasan inhibited the elevation of serum IL-1␤ levels observed in a mouse model of osteoarthritis (90), and reduced dextran sulfate sodium-induced murine colitis and Th1 T cell activation (91). 2) A sec- ond orally active caspase-1 inhibitor that has been recently described is VX-765. It has been shown to block IL-1␤ secretion in LPS-stimulated human PBMCs from familial cold autoinflammatory syndrome and control subjects (92). Altogether, these studies are promising and support a potential role for FIGURE 5. A model depicting the inflammatory pathways activated by bac- caspase-1 inhibitors in the treatment of autoinflammatory dis- terial pathogens and the role of caspase-12 as a negative regulator of the orders. Downloaded from caspase-1 pathway. Bacterial pathogens stimulate both the TLR system as well as the NLR/inflammasome pathway. TLRs signal predominantly through activation of NF-␬B, a transcription factor essential for the synthesis of inflam- ␤ Conclusions matory mediators including pro-IL-1 . NLRs activate caspase-1, which results Our understanding of the inflammatory caspases and their reg- in the processing and release of the proinflammatory cytokines IL-1␤ and IL- 18. Caspase-12 inhibits caspase-1 and dampens the levels of mature IL-1␤ and ulatory mechanisms has recently improved substantially. Mul-

IL-18, essential for pathogen clearance and sepsis resistance. tiple new players have now been identified to modulate the http://www.jimmunol.org/ function of these enzymes. The discovery of the caspase-12 polymorphism and the characterization of its function in sepsis sensitive to ER stress-induced apoptosis as caspase-12-profi- and the host response to pathogenic infection has emphasized cient cells (6, 24, 25, 85, 86). Murine caspase-12 appears to the essential role of these caspases in innate immunity. In par- function in inflammation similarly to the human caspase-12 allel, the identification of the NLR family and its regulation of full-length variant. We have recently shown that caspase-12-de- the inflammatory caspases has provided an important step for- ficient mice are more resistant to sepsis, and are able to clear ward in our knowledge of the tight and highly specific mechanisms of activation of these enzymes. Intense investigation is bacterial pathogens more efficiently than wild-type mice. by guest on September 29, 2021 Therefore, our results indicate that as in humans, caspase-12 is currently underway worldwide to answer the many remaining also deleterious in mice. Caspase-12 seems to exert its negative questions: what determines the specificity in inflammasome as- effects on inflammation through inhibition of caspase-1 (Fig. sembly and activation? Does inhibition of caspase-1 by Ϫ Ϫ 5). Caspase-12 / splenocytes secrete higher levels of mature caspase-12 in individuals of African descent provide an advan- IL-1␤ and IL-18 as compared with wild-type splenocytes, in tage in certain conditions? Are there other caspase-1 substrates response to various purified bacterial ligands (TLR/NOD2 li- essential for its effects in innate immunity? What are the roles of gands). Interestingly, the enzymatic function of caspase-12 is caspase-4 and -5 in inflammation? dispensable for its inhibitory effect on caspase-1, as mutation of the caspase-12 catalytic cysteine to alanine did not abrogate its ␤ References inhibitory effects on both caspase-1 catalysis and IL-1 process- 1. Nicholson, D. W. 1999. Caspase structure, proteolytic substrates, and function during (24). ing apoptotic cell death. Cell Death Differ. 6: 1028–1042. 2. Lamkanfi, M., W. Declercq, M. Kalai, X. Saelens, and P. Vandenabeele. 2002. Alice Therefore, caspase-12 could constitute a sepsis therapeutic in caspase land: a phylogenetic analysis of caspases from worm to man. Cell Death target for populations of African descent. In contrast, the find- Differ. 9: 358–361. ing that caspase-1 stimulation is necessary for sepsis survival 3. Salmena, L., B. Lemmers, A. Hakem, E. Matysiak-Zablocki, K. Murakami, P. Y. Au, D. M. Berry, L. Tamblyn, A. Shehabeldin, E. Migon, et al. 2003. 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