LAUSR

Summary Potassium (K+) efflux across the plasma membrane is thought to be an essential mechanism for ATP‐induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two‐pore domain K+ channel (K2P) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis‐induced lung inflammation. Adoptive transfer of Kcnk6−/− macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K+ efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti‐inflammatory therapies. Graphical Abstract Figure. No caption available. HighlightsMacrophage NLRP3 inflammasome activation is inhibited by potassium channel inhibitionTWIK2 is a potassium efflux channel required for NLRP3 inflammasome activationGenetic deletion of TWIK2 prevents endotoxemia‐induced inflammatory lung injuryP2X7 receptor and TWIK2 act in cooperation to regulate NLRP3 inflammasome activation &NA; Potassium efflux is required for NLRP3 inflammasome activation, but the channel mediating the efflux has remained elusive. Di et al. identify the potassium channel TWIK2 as a mediator of potassium efflux and NLRP3 activation in macrophages. Targeting TWIK2 could form the basis for therapeutic approaches in inflammatory injury.