Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis.
journal contributionposted on 10.08.2021, 09:30 authored by Lindsey Mayes-Hopfinger, Aura Enache, Jian Xie, Chou-Long Huang, Robert Köchl, Victor LJ Tybulewicz, Teresa Fernandes-Alnemri, Emad S Alnemri
The NLRP3 inflammasome mediates the production of proinflammatory cytokines and initiates inflammatory cell death. Although NLRP3 is essential for innate immunity, aberrant NLRP3 inflammasome activation contributes to a wide variety of inflammatory diseases. Understanding the pathways that control NLRP3 activation will help develop strategies to treat these diseases. Here we identify WNK1 as a negative regulator of the NLRP3 inflammasome. Macrophages deficient in WNK1 protein or kinase activity have increased NLRP3 activation and pyroptosis compared with control macrophages. Mice with conditional knockout of WNK1 in macrophages have increased IL-1β production in response to NLRP3 stimulation compared with control mice. Mechanistically, WNK1 tempers NLRP3 activation by balancing intracellular Cl- and K+ concentrations during NLRP3 activation. Collectively, this work shows that the WNK1 pathway has a critical function in suppressing NLRP3 activation and suggests that pharmacological inhibition of this pathway to treat hypertension might have negative clinical implications.
Crick (Grant ID: 10194, Grant title: Tybulewicz FC001194)
AnimalsCaspase 1ChloridesFemaleImidazolesImmunity, InnateInflammasomesInterleukin-1betaL-Lactate DehydrogenaseLipopolysaccharidesMacrophagesMaleMice, Inbred C57BLModels, BiologicalNLR Family, Pyrin Domain-Containing 3 ProteinNeutrophilsPotassiumProtein-Serine-Threonine KinasesPyroptosisPyrrolidinesTamoxifenWNK Lysine-Deficient Protein Kinase 1Tybulewicz FC001194Cell BiologyDevelopmental BiologyHuman Biology & PhysiologyImmunologyModel organismsSignalling & Oncogenes