Activation and regulation of the inflammasomes

Key Points

  • For the known inflammasomes, new cofactors such as caspase 11 and the NAIPs (NLR family, apoptosis inhibitory proteins) have been described. In addition, inflammasome-independent pathways for the processing of interleukin-1β (IL-1β), such as caspase 8 activation, have recently been described.

  • Cell-extrinsic signalling can regulate inflammasome activation. Signalling by pattern recognition or cytokine receptors primes the cell and induces NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pro-IL-1β expression, whereas signalling by type I interferons and activated T cells reduces inflammasome activation.

  • Energy levels, mitochondrial health and lysosomal compartmentalization are constantly under the surveillance of cellular health sensors such as the apoptosome and inflammasomes. These signalling platforms detect changes in cellular homeostasis and share many structural and functional similarities.

  • NLRP3 is strongly regulated by fluxes of K+, Cl and Ca2+. In addition, reactive oxygen species, autophagy and endoplasmic reticulum stress are important modulators of NLRP3 activity.

  • The inflammasomes are regulated by pyrin domain- or CARD (caspase activation and recruitment domain)-only proteins, which sequester the signalling molecules. Other proteins that are known to regulate apoptosis also have a role in inflammasome signalling.

  • Understanding the regulatory mechanisms of inflammasome activation will facilitate the development of new classes of drugs that target the inflammasomes.

Abstract

Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform — the apoptosome — that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy.

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Figure 1: Canonical and non-canonical activation of IL-1β.
Figure 2: Extracellular signals regulate the inflammasomes.
Figure 3: Ion fluxes and cell stress regulate the NLRP3 inflammasome.

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Acknowledgements

The authors would like to thank C. M. De Nardo and B. G. Monks for critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (NIH) and the Deutsche Forschungsgemeinschaft (DFG), Germany (to E.L.), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA (to T.S.X.). E.L. is a member of the excellence cluster ImmunoSensation in Bonn, Germany.

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Glossary

ASC

An adaptor protein that was originally found to form protein precipitates in apoptotic cells that are termed protein specks.

Pyroptosis

A rapid form of cell death following caspase 1 activation, which shares characteristics with both apoptosis (such as DNA fragmentation) and necrosis (such as cell swelling and rupture).

Apoptosome

A large multimeric protein complex of apoptotic protease-activating factor 1 (APAF1) that recognizes cytochrome c release from damaged mitochondria and activates caspase 9.

Death-fold domains

Commonly found in proteins that are involved in cell death pathways and in inflammasomes. The four main death-fold domains — the pyrin domain, caspase activation and recruitment domain (CARD), death domain and death effector domain — associate with each other through homotypic interactions.

NOD-like receptor

(NLR). A protein that contains amino-terminal pyrin, caspase-recruitment domains or other signalling domains, followed by a NACHT domain and carboxy-terminal leucine-rich repeats. Some NLR proteins are involved in forming inflammasomes.

Non-canonical NLRP3 inflammasome

An inflammasome-like complex containing NLRP3 (NOD-, LRR- and pyrin domain-containing 3), the adaptor protein ASC, caspase 1 and caspase 11. The term 'non-canonical inflammasome' is used loosely to describe an inflammasome-like complex that does not conform to the three 'canonical' components of a canonical inflammasome: an inflammasome sensor molecule, ASC and caspase 1. Two other non-canonical inflammasomes have also been described so far: one containing dectin 1, MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), ASC and caspase 8 (termed the non-canonical caspase 8 inflammasome), and a caspase 11-activating platform that has not yet been fully described.

Ripoptosome

A cytosolic multiprotein complex that induces cell death following genotoxic stress or depletion of inhibitor of apoptosis protein (IAP). The core ripoptosome contains receptor-interacting protein 1 (RIP1), FAS-associated death domain protein (FADD) and caspase 8, but it can also recruit other proteins such as RIP3.

Amyloid-β

An endogenous peptide that is generated by proteases in the brain. It is prone to aggregation and plaque formation. Amyloid-β plaques are a hallmark of Alzheimer's disease and can activate the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome.

Cryopyrin-associated periodic syndrome

(CAPS). Characterized by NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome hyperactivity and the excessive release of interleukin-1β, which leads to an autoinflammatory disease phenotype with periodic fever episodes, urticaria and often severe arthritis.

MicroRNA

Small, endogenous RNA molecules that can recruit the RNA-induced silencing complex to an mRNA, leading to inhibition of translation or to degradation of the mRNA.

Autophagy

A homeostatic process during which cellular components are recycled through the lysosomal compartment. Its main triggers include nutrient starvation, defective organelles and infection.

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Latz, E., Xiao, T. & Stutz, A. Activation and regulation of the inflammasomes. Nat Rev Immunol 13, 397–411 (2013). https://doi.org/10.1038/nri3452

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