KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation.
Fiche publication
Date publication
décembre 2023
Journal
Science immunology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr RICCI Roméo, Dr SUMARA Izabela
Tous les auteurs :
Ran L, Ye T, Erbs E, Ehl S, Spassky N, Sumara I, Zhang Z, Ricci R
Lien Pubmed
Résumé
Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin-associated periodic syndrome (CAPS), caused by mutations in the gene, develop autoinflammation triggered by nonantigenic cues such as from the environment. 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, lowered the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increased NLRP3-dependent inflammation. Myeloid-specific deletion of protected mice from gouty arthritis. Mechanistically, activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux and promotes NLRP3 inflammasome activation. Activation of PIEZO signaling was sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Last, pharmacological inhibition of KCNN4 alleviated autoinflammation in cells of patients with CAPS and in mice bearing a CAPS mutation. Thus, PIEZO-dependent mechanical inputs boost inflammation in NLRP3-dependent diseases, including CAPS.
Mots clés
Humans, Animals, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, genetics, Inflammasomes, metabolism, Mechanotransduction, Cellular, Cryopyrin-Associated Periodic Syndromes, genetics, Inflammation, Intermediate-Conductance Calcium-Activated Potassium Channels, Ion Channels, genetics
Référence
Sci Immunol. 2023 12 22;8(90):eadf4699