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The Two pore Potassium Channel THIK-1 Regulates NLRP3 Inflammasome Activation
The NLRP3 (NLR family, pyrin domain containing 3) inflammasome is a multiāprotein complex responsible for the activation of caspaseā1 and the subsequent cleavage and activation of the potent proinflammatory cytokines ILā1Ī² and ILā18, and pyroptotic cell death. NLRP3 is implicated as a driver of inflammation in a range of disorders including neurodegenerative diseases, type 2 diabetes, and atherosclerosis. A commonly reported mechanism contributing to NLRP3 inflammasome activation is potassium ion (K(+)) efflux across the plasma membrane. Identification of K(+) channels involved in NLRP3 activation remains incomplete. Here, we investigated the role of the K(+) channel THIKā1 in NLRP3 activation. Both pharmacological inhibitors and cells from THIKā1 knockout (KO) mice were used to assess THIKā1 contribution to macrophage NLRP3 activation in vitro. Pharmacological inhibition of THIKā1 inhibited caspaseā1 activation and ILā1Ī² release from mouse boneāmarrowāderived macrophages (BMDMs), mixed glia, and microglia in response to NLRP3 agonists. Similarly, BMDMs and microglia from THIKā1 KO mice had reduced NLRP3ādependent ILā1Ī² release in response to P2X7 receptor activation with ATP. Overall, these data suggest that THIKā1 is a regulator of NLRP3 inflammasome activation in response to ATP and identify THIKā1 as a potential therapeutic target for inflammatory disease