The Two pore Potassium Channel THIK-1 Regulates NLRP3 Inflammasome Activation

Samuel Drinkall, Catherine B. Lawrence, Bernadino Ossola, Samuel Russell, Clare Bender, Nicola B. Brice, Lee A Dawson, Michael Harte, David Brough

Research output: Contribution to journalArticlepeer-review

Abstract

The NLRP3 inflammasome is a multi-protein complex responsible for the activation of caspase-1 and the subsequent cleavage and activation of the potent proinflammatory cytokines IL-1β and IL- 18, 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 THIK-1 in NLRP3 activation. Both pharmacological inhibitors and cells from THIK-1 knockout mice were used to assess THIK-1 contribution to macrophage NLRP3 activation in vitro. Pharmacological inhibition of THIK-1 inhibited caspase-1 activation and IL-1β release from mouse bone-marrow derived macrophages (BMDMs), mixed glia, and microglia in response to NLRP3 agonists. Similarly, BMDMs and microglia from THIK-1 knockout mice had reduced NLRP3-dependent IL-1β release in response to P2X7 receptor activation with ATP. Overall, these data suggest that THIK-1 is a regulator of NLRP3 inflammasome activation in response to ATP and identify THIK-1 as a potential therapeutic target for inflammatory disease.
Original languageEnglish
JournalGLIA
Publication statusAccepted/In press - 21 Mar 2022

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