Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets

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.