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  • Review Article
  • Published:

Converging roles of caspases in inflammasome activation, cell death and innate immunity

Nature Reviews Immunology volume 16, pages 7–21 (2016)Cite this article

Subjects

Key Points

  • Caspases have multifaceted roles in the immune system. They form structurally diverse and dynamic complexes to drive cell death and inflammation.

  • Inflammatory caspases — caspase 1, caspase 4, caspase 5 and caspase 11 — mediate inflammasome-associated secretion of interleukin-1β (IL-1β) and IL-18 and initiate pyroptosis.

  • The inflammatory caspase 12 has enigmatic roles in the immune system.

  • The apoptotic caspase 8 contributes to the initiation of inflammation by modulating nuclear factor-κB signalling and promotes direct or indirect cleavage of pro-IL-1β and pro-IL-18, but also has a role in the inhibition of inflammation by blocking inflammasome activation, interferon responses and necroptosis.

  • The functional roles of caspases and the cytoskeleton are linked to cell-autonomous immunity, which contributes to the clearance of pathogens.

  • The converging and interconnected roles of caspases challenge the existing functional classification of the caspase family members.

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 inflammasome-associated cytokines interleukin-1β (IL-1β) and IL-18, 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 that highlight new aspects of this family of cysteine proteases in innate immunity.

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Figure 1: Caspase 1 and the canonical inflammasomes.
Figure 2: Inflammatory caspases and the non-canonical NLRP3 inflammasome.
Figure 3: Caspase 8 mediates initiation of NF-κB signalling and maturation of IL-1β.
Figure 4: Inhibition of inflammation by caspase 8 and other apoptotic caspases.

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Acknowledgements

Research studies from the authors' laboratory are supported by the US National Institutes of Health (AR056296, CA163507 and AI101935 to T.-D.K.), the American Lebanese Syrian Associated Charities (to T.-D.K.) and the National Health and Medical Research Council of Australia (NHMRC/R.G. Menzies Early Career Fellowship to S.M.M.). The authors apologize to their colleagues whose work was not cited owing to space limitations.

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  1. Department of Immunology, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Si Ming Man & Thirumala-Devi Kanneganti

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Glossary

Inflammasomes

Multi-protein complexes that activate caspase 1 to induce processing of pro-interleukin-1β and pro-interleukin-18 and to drive pyroptosis.

Pyroptosis

An inflammatory and lytic form of programmed cell death mediated by inflammatory caspases.

Apoptosis

A non-inflammatory form of programmed cell death mediated by apoptotic caspases. Apoptotic cells exhibit membrane blebbing (but have an intact cell membrane), DNA fragmentation and cell shrinkage.

Death receptors

A subset of receptors within the tumour necrosis factor receptor superfamily that, on binding to their ligands, convey cell death signals.

FLICE-like inhibitory protein

(FLIP). The long isoform (FLIPL) heterodimerizes with pro-caspase 8 to inhibit apoptosis and potentially inhibits necroptosis. By contrast, the short isoform (FLIPS) promotes necroptosis.

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.

Alarmin

A damage-associated molecular pattern that is released by damaged or necrotic cells in response to infection or injury. Alarmins are recognized by pattern-recognition receptors to further activate immune cells.

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 and caspase 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 and AIM2 inflammasomes.

Guanylate-binding proteins

A group of interferon-inducible GTPases produced by the host cell that often target pathogen-containing vacuoles, contributing to the release of pathogens from the vacuole and mediating pathogen killing.

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.

Inhibitor of apoptosis proteins

(IAPs). A family of proteins that have multiple functions, including inhibition of apoptosis by binding to apoptotic caspases, E3 ubiquitin ligase activity, regulation of MAPK and NF-κB signalling pathways and regulation of signal transduction by pattern-recognition receptors.

Second mitochondrial-derived activator of caspases

(SMAC). Endogenous antagonist of inhibitor of apoptosis proteins (IAPs) released from mitochondria in response to death stimuli. SMAC binds and degrades XIAP, cIAP1 and cIAP2, resulting in increased caspase activation.

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.

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Man, S., Kanneganti, TD. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol 16, 7–21 (2016). https://doi.org/10.1038/nri.2015.7

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