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Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets

Nature Reviews Drug Discovery volume 23, pages 43–66 (2024)Cite this article

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Abstract

Diseases associated with chronic inflammation constitute a major health burden across the world. As central instigators of the inflammatory response to infection and tissue damage, inflammasomes — and the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome in particular — have emerged as key regulators in diverse rheumatic, metabolic and neurodegenerative diseases. Similarly to other inflammasome sensors, NLRP3 assembles a cytosolic innate immune complex that activates the cysteine protease caspase-1, which in turn cleaves gasdermin D (GSDMD) to induce pyroptosis, a regulated mode of lytic cell death. Pyroptosis is highly inflammatory, partly because of the concomitant extracellular release of the inflammasome-dependent cytokines IL-1β and IL-18 along with a myriad of additional danger signals and intracellular antigens. Here, we discuss how NLRP3 and downstream inflammasome effectors such as GSDMD, apoptosis-associated speck-like protein containing a CARD (ASC) and nerve injury-induced protein 1 (NINJ1) have gained significant traction as therapeutic targets. We highlight the recent progress in developing small-molecule and biologic inhibitors that are advancing into the clinic and serving to harness the broad therapeutic potential of modulating the NLRP3 inflammasome.

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Fig. 1: Overview of human inflammasomes with their respective stimuli and expression profiles.
Fig. 2: Molecular mechanisms driving NLRP3 inflammasome activation.
Fig. 3: Binding pocket of CRID3 and model for NLRP3 inflammasome activation.
Fig. 4: Therapeutic targets and inhibitors of the NLRP3 inflammasome pathway.

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Acknowledgements

The authors apologize to colleagues whose work was not cited because of space constraints. This work was supported by the Fund for Scientific Research (FWO)-Flanders grant G017121N and European Research Council Grant 101101075 (PyroScreen) to M.L.

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  1. Laboratory of Medical Immunology, Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium

    Lieselotte Vande Walle & Mohamed Lamkanfi

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Vande Walle, L., Lamkanfi, M. Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets. Nat Rev Drug Discov 23, 43–66 (2024). https://doi.org/10.1038/s41573-023-00822-2

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