KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation

Abstract Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop auto-inflammation triggered by non-antigenic, e.g. environmental cues. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowers the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increases NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protects mice from gouty arthritis. Activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux promoting NLRP3 inflammasome activation. Activation of PIEZO signaling is sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Finally, pharmacologic inhibition of KCNN4 alleviates auto-inflammation in CAPS patient cells and in CAPS-mimicking mice. Thus, PIEZO-dependent mechanical inputs augment inflammation in NLRP3-dependent diseases including CAPS. One Sentence Summary PIEZO-mediated mechanotransduction stimulates KCNN4-dependent potassium efflux to potentiate NLRP3 inflammasome activation.