Caspases in Inflammation and Immunity


Two of the main challenges that eukaryotic multicellular organisms faced during evolution were to cope with invading microorganisms and to eliminate infected cells. The immune system evolved to handle both tasks. Intertwined with immunity is programmed cell death that tailors the immune response and provides an effective way to remove infected cells. Caspases, effectors of inflammation and programmed cell death cascades, are perfectly suited to regulate the host response to invaders and injury. Their activity as inflammatory and killer proteases is regulated by direct binding to sensors of pathogens or danger, they can be modified following activation of signalling cascades by feedback mechanisms to terminate the inflammatory response and control cell survival, and they associate with coactivators and corepressors whose expression is closely linked to the needs of the cell.

Key concepts

  • Cell death and innate immunity are ancient evolutionarily conserved processes that utilize a number of related effectors and parallel signal transduction mechanisms.

  • Innate immunity provides first line defences against pathogens and acts as a sentinel that primes adaptive immunity.

  • Innate immunity depends on evolutionarily conserved germline‐encoded pattern recognition receptors (PRRs) that ‘sense’ pathogen‐associated molecular patterns (PAMPs) and ‘danger’ signals.

  • The role of caspases in innate immunity is conserved through evolution.

  • Caspase‐1, the prototypical member of the inflammatory caspase subfamily, contributes to host defence through different interrelated mechanisms, notably cell repair, inflammation and cell death.

  • Caspase‐1 activity is necessary for host resistance to pathogens; however, when deregulated, it is at the basis of multiple inflammatory diseases.

  • Inflammatory caspases are activated in NLR‐scaffolded multiprotein complexes termed ‘inflammasomes’ that are reminiscent of the apoptosome. Caspase‐12, an inflammatory caspase related to caspase‐1, is an endogenous inhibitor of the inflammasome.

  • Apoptosis tailors adaptive immunity. Mutations in Casp‐8 and Casp‐10 cause autoimmune lymphoproliferative syndrome (ALPS).

  • Excessive apoptotic caspase activity contributes to the pathogenesis of inflammatory diseases such as severe sepsis.

Keywords: caspases; inflammation; immunity; pattern recognition receptors; inflammatory and autoimmune diseases

Figure 1.

Insect and mammalian innate immune pathways. Antimicrobial peptides (AMPs) and cytokines are the main effectors of insect and mammalian immunity, respectively. The pathways leading to their production are evolutionarily conserved. Mammalian TLR and TNF‐R signalling components are related to those operating in insect Toll and Imd pathways. Few modifications to the pathways and expansion of adaptors/signalling molecules occurred through evolution: (1) caspase‐8 does not process NFκB proteins in mammalian cells nonetheless its function in modulating NFκB activity downstream of the TNF receptor is conserved. (2) Toll is not a PRR and the insect path to AMP production requires the proteolytic processing of the cytokine spaetzle. Although TLRs are PRRs and could trigger cytokine and AMP production directly, caspase‐1 processing of pro‐IL‐1β in response to pathogen sensing results in signal transduction to AMP production via the IL‐1 receptor, which shares with TOLL and TLRs the TIR domain and downstream activation cascade. (3) A PRR (PGRP‐LC) initiates the Imd pathway. In contrast, TNFR signalling is activated following a TNFα autocrine loop. (4) Apoptosis does not occur following IMD‐DREDD activation while it is induced by TNFα.

Figure 2.

A parallel between apoptosis and innate immunity. (a) Nod‐like receptors (NLRs) share with APAF‐1 a tripartite structure that mediates ligand sensing, nucleotide binding and oligomerization and recruitment of caspases. The NLR family consists of the NOD, NALP and IPAF subfamilies. In addition, it includes the MHC II gene transactivator CIITA. AIM2 is a novel cytosolic deoxyribonucleic acid (DNA) sensor that contains a N‐terminal pyrin domain (PYD) and assembles an inflammasome. ASC and Cardinal are inflammasome adaptors. (b) The inflammasome is reminiscent of the apoptosome. The apoptosome is scaffolded by the protein APAF‐1 and assembles in response to cytochrome c release from the mitochondria to activate caspase‐9 and apoptosis cascades. NLR proteins scaffold the inflammasome, which is activated by a wide spectrum of triggers including PAMPs (pathogen nucleic acids, flagellin) and DAMPs (ATP, ionic perturbations, crystals and protein aggregates). The inflammasomes recruit and activate caspase‐1 to induce inflammation, cell survival or pyroptosis. The Nodosome, which is related to the TNFR signalosome, is linked to caspases indirectly. It is activated by PGN derivatives and signals through the kinase RIP2 to induce inflammation and antimicrobial responses.

Figure 3.

Characteristics of the inflammatory caspases. (a) Chromosomal arrangement of the inflammatory caspase genes on human chromosome 11 and on a syntenic region on mouse chromosome 9. Genes encoding the CARD‐only proteins COP and ICEBERG are present only in humans. (b) Domain organization of the inflammatory caspases. CARD, caspase‐recruitment domain; p20, large subunit (20 kDa) and p10, small subunit (10 kDa). (c) The crystal structure of caspase‐1 is shown. Caspase‐1 inhibitors are depicted in red and caspase‐1 activators in green. (d) Inflammatory caspases preference for the substrate cleavage site. With the exception of caspase‐12, the inflammatory caspases prefer a bulky hydrophobic residue at position P4 C‐terminus of the scissile bond that invariably occurs at an aspartate (P1).

Figure 4.

Mutations in the initiator caspase‐8 and caspase‐10 result in autoimmune lymphoproliferation syndromes (ALPS). Caspase‐8 and caspase‐10 are recruited to the death‐inducing signalling complex (DISC) on binding of the trimeric FAS ligand (FASL) to its receptor FAS. Caspase recruitment and activation occurs via the adaptor protein FADD (Fas‐associated death domain‐containing protein), and is essential for lymphocyte apoptosis. Autosomal recessive mutations in FASL and FAS are found in the gld/gld and lpr/lpr mice, respectively. In humans, mutations in FASL, FAS and caspase‐8 and caspase‐10 are present in ALPS patients.



Bidere N, Su HC and Lenardo MJ (2006) Genetic disorders of programmed cell death in the immune system. Annual Review of Immunology 24: 321–352.

Boatright KM, Renatus M, Scott FL et al. (2003) A unified model for apical caspase activation. Molecular Cell 11: 529–541.

Bruey JM, Bruey‐Sedano N, Luciano F et al. (2007) Bcl‐2 and Bcl‐XL regulate proinflammatory caspase‐1 activation by interaction with NALP1. Cell 129: 45–56.

Cohen PL and Eisenberg RA (1991) Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annual Review of Immunology 9: 243–269.

DeYoung BJ and Innes RW (2006) Plant NBS‐LRR proteins in pathogen sensing and host defense. Nature Immunology 7: 1243–1249.

Dinarello CA (1996) Biologic basis for interleukin‐1 in disease. Blood 87: 2095–2147.

Hoffman HM, Rosengren S, Boyle DL et al. (2004) Prevention of cold‐associated acute inflammation in familial cold autoinflammatory syndrome by interleukin‐1 receptor antagonist. Lancet 364: 1779–1785.

Hotchkiss RS and Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nature Review of Immunology 6: 813–822.

Hsu LC, Ali SR, McGillivray S et al. (2008) A NOD2‐NALP1 complex mediates caspase‐1‐dependent IL‐1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proceedings of the National Academy of Sciences of the USA 105: 7803–7808.

Hugot JP, Chamaillard M, Zouali H et al. (2001) Association of NOD2 leucine‐rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599–603.

Kastner DL (2005) Hereditary periodic Fever syndromes. Hematology. American Society of Hematology. Education Program 74–81.

Kawai T and Akira S (2006) TLR signaling. Cell Death and Differentiation 13: 816–825.

Keller M, Ruegg A, Werner S and Beer HD (2008) Active caspase‐1 is a regulator of unconventional protein secretion. Cell 132: 818–831.

Krammer PH, Arnold R and Lavrik IN (2007) Life and death in peripheral T cells. Nature Review of Immunology 7: 532–542.

Labbé K and Saleh M (2008) Cell death in the host response to pathogens. Cell Death and Differentiation 15: 1339–1349.

LeBlanc PY, Rutherford G, Doiron N et al. (2008) Caspase‐12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host & Microbe 3: 146–157.

Lee SK and Surh CD (2005) Role of interleukin‐7 in bone and T‐cell homeostasis. Immunological Review 208: 169–180.

Lemaitre B and Hoffmann J (2007) The host defense of Drosophila melanogaster. Annual Review of Immunology 25: 697–743.

Martinon F, Pétrilli V, Mayor A, Tardivel A and Tschopp J (2006) Gout‐associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081): 237–241.

McIntire CR, Yeretssian G and Saleh M (2009) Inflammasomes in infection and inflammation. Apoptosis 14(4): 522–535.

Medzhitov R, Preston‐Hurlburt P and Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394–397.

Miceli‐Richard C, Lesage S, Rybojad M et al. (2001) CARD15 mutations in Blau syndrome. Nature Genetics 29: 19–20.

Opferman JT (2008) Apoptosis in the development of the immune system. Cell Death and Differentiation 15: 234–242.

Oppenheim JJ and Yang D (2005) Alarmins: chemotactic activators of immune responses. Current Opinion in Immunology 17: 359–365.

Roy S, Sharom JR, Houde C et al. (2008) Confinement of caspase‐12 proteolytic activity to autoprocessing. Proceedings of the National Academy of Sciences of the USA 105: 4133–4138.

Saleh M (2006) Caspase‐1 builds a new barrier to infection. Cell 126: 1028–1030.

Saleh M, Mathison JC, Wolinski MK et al. (2006) Enhanced bacterial clearance and sepsis resistance in caspase‐12 deficient mice. Nature 440: 1064–1068.

Saleh M, Vaillancourt JP, Graham RK et al. (2004) Differential modulation of endotoxin responsiveness by human caspase‐12 polymorphisms. Nature 429: 75–79.

Shao W, Yeretssian G, Doiron K, Hussain SN and Saleh M (2007) The caspase‐1 digestome identifies the glycolysis pathway as a target during infection and septic shock. Journal of Biological Chemistry 282: 36321–36329.

Thornberry NA, Bull HG, Calaycay JR et al. (1992) A novel heterodimeric cysteine protease is required for interleukin‐1 beta processing in monocytes. Nature 356(6372): 768–774.

Villani AC, Lemire M, Fortin G et al. (2009) Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nature Genetics 41: 71–76.

Further Reading

Ferrandon D, Imler JL, Hetru C and Hoffmann JA (2007) The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections. Nature Review of Immunology 7(11): 862–874.

Green DR (2008) Fas Bim boom! Immunity 28: 141–143.

Matzinger P (2002) The danger model: a renewed sense of self. Science 296: 301–305.

Scott AM and Saleh M (2007) The inflammatory caspases: guardians against infections and sepsis. Cell Death and Differentiation 14: 23–31.

Yeretssian G, Labbe K and Saleh M (2008) Molecular regulation of inflammation and cell death. Cytokine 43: 380–390.

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LeBlanc, Philippe M, and Saleh, Maya(Sep 2009) Caspases in Inflammation and Immunity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021990]