Abstract
Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.
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Acknowledgements
R.C.C. thanks K. Wilhelmson for helpful discussions of NLRP3 inhibitors.
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Both authors contributed equally to the preparation of this manuscript.
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Competing interests
R.C.C. and K.S. are co-inventors on patent applications for NLRP3 inhibitors that have been licensed to Inflazome Ltd, a company acquired by Roche. K.S. served on the scientific advisory board of Inflazome (2016–2017) and Quench Bio, USA (2018–2021) and serves on a scientific advisory board for Novartis, Switzerland (since 2020). R.C.C. is a consultant for BioAge Labs, USA (since 2020) and serves on the scientific advisory board of Viva In Vitro diagnostics, Spain (since 2024).
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Nature Reviews Immunology thanks Fayyaz Sutterwala, who co-reviewed with Diogo Valadares, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Related links
Noncanonical inflammasomes: signalling, pyroptosis and NETosis in host defence: https://youtu.be/-etkTCbnB1w?si=NVx3csYGC-xGF0y3
The inflammasome signalling pathway updated: https://youtu.be/-FNFZ9F1eB4?si=K6OSBez1AtWJKLnR
Supplementary information
Glossary
- Alarmins
-
Host molecules that are released or exposed upon cell damage or cell death, which trigger immune responses.
- Allosteric inhibitors
-
Compounds that bind to an enzyme at a site other than its active site, thereby rendering the enzyme unable to bind to its substrate.
- Canonical inflammasomes
-
Multi-protein signalling complexes that activate caspase 1 (CASP1) to induce inflammatory responses and pyroptosis.
- Liquid–liquid phase separation
-
A form of phase transition in which one homogeneous solution spontaneously separates into two distinct liquids, caused by self-aggregation of a molecule in the dense phase.
- Monogenic autoinflammatory diseases
-
Rare diseases caused by single gene mutations that elicit hyperactive innate immune responses, resulting in periodic or chronic inflammation.
- Nanobodies
-
Small, single-domain antibodies containing a single, monomeric, variable antibody domain that binds to an antigen.
- Non-canonical inflammasomes
-
Protein–lipid assemblies that activate caspase 4 (CASP4) and CASP5 in humans, and CASP11 in mice, to induce inflammatory responses and pyroptosis.
- Pyroptosis
-
Programmed cell lysis mediated by gasdermin family members, often occurring downstream of inflammasomes.
- Tool compound
-
A small molecule with a defined structure and well-characterized activity.
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Coll, R.C., Schroder, K. Inflammasome components as new therapeutic targets in inflammatory disease. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01075-9
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DOI: https://doi.org/10.1038/s41577-024-01075-9
