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  • Review Article
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The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases

Nature Reviews Cardiology volume 21, pages 219–237 (2024)Cite this article

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Abstract

An intense, stereotyped inflammatory response occurs in response to ischaemic and non-ischaemic injury to the myocardium. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a finely regulated macromolecular protein complex that senses the injury and triggers and amplifies the inflammatory response by activation of caspase 1; cleavage of pro-inflammatory cytokines, such as pro-IL-1β and pro-IL-18, to their mature forms; and induction of inflammatory cell death (pyroptosis). Inhibitors of the NLRP3 inflammasome and blockers of IL-1β and IL-18 activity have been shown to reduce injury to the myocardium and pericardium, favour resolution of the inflammation and preserve cardiac function. In this Review, we discuss the components of the NLRP3 inflammasome and how it is formed and activated in various ischaemic and non-ischaemic cardiac pathologies (acute myocardial infarction, cardiac dysfunction and remodelling, atherothrombosis, myocarditis and pericarditis, cardiotoxicity and cardiac sarcoidosis). We also summarize current preclinical and clinical evidence from studies of agents that target the NLRP3 inflammasome and related cytokines.

Key points

  • The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a macromolecular, intracellular structure that functions as a sensor for injury.

  • NLRP3 inflammasome activation amplifies the inflammatory response and tissue injury by regulating the processing and release of IL-1β and IL-18 and causing cell death by pyroptosis.

  • Preclinical studies with genetically modified mouse models and the use of targeted inhibitors have shown that inhibiting activation of the NLRP3 inflammasome reduces inflammatory injury and adverse remodelling.

  • Colchicine, a non-selective NLRP3 inflammasome inhibitor, has been shown to be efficacious in the treatment of pericarditis and in reducing atherothrombotic risk in patients with coronary artery disease.

  • IL-1 blockers have been shown in phase Ib–III trials to reduce cardiovascular risk and morbidity across a wide range of cardiovascular diseases, including myocardial infarction, heart failure, acute myocarditis and recurrent pericarditis.

  • Targeted NLRP3 inflammasome inhibitors and blockers of IL-18 and IL-6, downstream of IL-1, are in clinical testing for various cardiovascular diseases.

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Fig. 1: Activation of the NLRP3 inflammasome pathways in cardiomyocytes.
Fig. 2: Temporal expression of the NLRP3 inflammasome components and window of opportunity for effective inhibition in ischaemia–reperfusion injury.
Fig. 3: Prevention of NLRP3 inflammasome formation reduces damage in animal models of ischaemia–reperfusion injury.
Fig. 4: Role of IL-1β in acute injury and progression to heart failure.
Fig. 5: Mechanism of action of NLRP3 inflammasome inhibitors tested in experimental models of ischaemic and non-ischaemic injury.
Fig. 6: Role of IL-1α and IL-1β in the pathophysiology of recurrent pericarditis.
Fig. 7: Overview of phase II–III trials of IL-1 blockers in acute myocardial infarction and heart failure.

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Acknowledgements

S.T. is supported by an NIH grant HL150115. A.A. is supported by NIH grants AG076360, HL139943 and HL150115.

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  1. Robert M. Berne Cardiovascular Research Center and Division of Cardiology, Department of Medicine, University of Virginia, Charlottesville, VA, USA

    Stefano Toldo & Antonio Abbate

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S.T. has received research grants from Cardiol, Kiniksa and Olatec. A.A. has served as a consultant to Cardiol, Implicit Bioscience, Janssen, Kiniksa, Novo Nordisk, Olatec, R-Pharm, Sanofi and Serpin Pharma.

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Toldo, S., Abbate, A. The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol 21, 219–237 (2024). https://doi.org/10.1038/s41569-023-00946-3

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