The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Abstract

The discovery that NLRP3 (which encodes NOD-, LRRand pyrin domain-containing protein 3) gain-offunction mutations cause the dominantly inherited autoinflammatory disease known as cryopyrin-associated periodic syndrome (CAPS) represented a major advance in inflammation research [1][2][3] . CAPS belongs to a group of diseases with varied severity that includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (also known as neonatal-onset multisystem inflammatory disorder). Early studies linked NLRP3 to inflammation mediated by the cytokine IL-1 and revealed the involvement of NLRP3 in autoinflammatory diseases, which has been reviewed in depth elsewhere 4,5 . In parallel, the discovery that NLRP1 can form a complex with activated caspase 1 termed the inflammasome 6 , followed by the revelation that NLRP3 can perform a similar function, provided a molecular basis to explain the CAPS phenotype 7 . Beyond the monogenic autoinflammatory diseases in humans, NLRP3 was shown to affect a wide range of disease models in mice, highlighting the potential application of NLRP3-targeted therapies for these diseases.The past decade has witnessed a burgeoning appreciation of inflammasomes as critical innate immune components that orchestrate host immune homeostasis. This Review focuses on the recent advances in our understanding of the activation and intrinsic regulation of the NLRP3 inflammasome machinery, as well as the emerging pharmacological approaches that target the NLRP3 inflammasome and show potential for clinical translation. The NLRP3 inflammasome: an overviewThe NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor (ASC; also known as PYCARD) and an effector (caspase 1). NLRP3 is a tripartite protein that contains an amino-terminal pyrin domain (PYD), a central NACHT domain (domain present in NAIP, CIITA, HET-E and TP1) and a carboxy-terminal leucine-rich repeat domain (LRR domain). The NACHT domain has ATPase activity that is vital for NLRP3 self-association and function 8 , whereas the LRR domain is thought to induce autoinhibition by folding back onto the NACHT domain. ASC has two protein interaction domains, an aminoterminal PYD and a carboxy-terminal caspase recruitment domain (CARD). Full-length caspase 1 has an amino-terminal CARD, a central large catalytic domain (p20) and a carboxy-terminal small catalytic subunit domain (p10). Upon stimulation, NLRP3 oligomerizes through homotypic interactions between NACHT domains (Fig. 1). Oligomerized NLRP3 recruits ASC through homotypic PYD-PYD interactions and nucleates helical ASC filament formation, which also occurs through PYD-PYD interactions. Multiple ASC filaments coalesce into a single macromolecular focus, known as an ASC speck [9][10][11] . Assembled ASC recruits caspase 1 through CARD-CARD interactions and enables proximity-induced caspase 1 self-cleavage and activation. Caspase 1 clustered on ASC self-cleaves at the linker between p20 and p10 to generate a complex of p33 (...

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