Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets.

Autor: Vande Walle L; Laboratory of Medical Immunology, Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium., Lamkanfi M; Laboratory of Medical Immunology, Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium. mohamed.lamkanfi@ugent.be.
Jazyk: angličtina
Zdroj: Nature reviews. Drug discovery [Nat Rev Drug Discov] 2024 Jan; Vol. 23 (1), pp. 43-66. Date of Electronic Publication: 2023 Nov 29.
DOI: 10.1038/s41573-023-00822-2
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: