Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming

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.