Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets

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. Inflammasomes are central instigators of the inflammatory response to infection and tissue damage and key regulators in diverse diseases. Here, the authors describe signalling mechanisms that regulate the NLRP3 inflammasome pathways and recent progress in the development of inhibitors and agonists that are advancing into the clinic.