Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming

TLDR

The NLRP3 inflammasome is a key regulator of inflammation and immunity, forming a multimolecular platform that activates caspases to secrete cytokines such as IL‑1β, yet the mechanisms controlling its assembly remain incompletely understood. The study investigates how chloride channel activity drives the formation of dynamic ASC oligomers and inflammasome specks that are inactive without potassium efflux, thereby providing mechanistic insight into inflammasome activation and inflammatory regulation. Cl‑efflux alone induces reversible, NLRP3‑dependent ASC specks that are inactive yet prime IL‑1β release upon subsequent K⁺ efflux, while NEK7 serves as a K⁺ sensor that associates with NLRP3 only after K⁺ efflux to activate the inflammatory complex.

Abstract

The NLRP3 inflammasome is an important regulator of inflammation and immunity. It is a multimolecular platform formed within cells that facilitates the activation of proinflammatory caspases to drive secretion of cytokines such as interleukin-1β (IL-1β). Knowledge of the mechanisms regulating formation of the NLRP3 inflammasome is incomplete. Here we report Cl- channel-dependent formation of dynamic ASC oligomers and inflammasome specks that remain inactive in the absence of K+ efflux. Formed after Cl- efflux exclusively, ASC specks are NLRP3 dependent, reversible, and inactive, although they further prime inflammatory responses, accelerating and enhancing release of IL-1β in response to a K+ efflux-inducing stimulus. NEK7 is a specific K+ sensor and does not associate with NLRP3 under conditions stimulating exclusively Cl- efflux, but does after K+ efflux, activating the complex driving inflammation. Our investigation delivers mechanistic understanding into inflammasome activation and the regulation of inflammatory responses.