The two pore potassium channel THIK‐1 regulates NLRP3 inflammasome activation

The NLRP3 (NLR family, pyrin domain containing 3) 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 infl...

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Published in:	Glia Vol. 70; no. 7; pp. 1301 - 1316
Main Authors:	Drinkall, Samuel, Lawrence, Catherine B., Ossola, Bernadino, Russell, Samuel, Bender, Clare, Brice, Nicola B., Dawson, Lee A., Harte, Michael, Brough, David
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-07-2022 Wiley Subscription Services, Inc
Subjects:	Adenosine Triphosphate - metabolism Animals Arteriosclerosis Atherosclerosis ATP Bone marrow Caspase Caspase 1 - metabolism Cell activation Cell death Cytokines Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 Efflux inflammasome Inflammasomes Inflammasomes - metabolism inflammation Inflammatory diseases Interleukin-1beta - metabolism interleukin‐1 Macrophages Mice Mice, Inbred C57BL Mice, Knockout Microglia Neurodegenerative diseases NLR Family, Pyrin Domain-Containing 3 Protein - genetics NLR Family, Pyrin Domain-Containing 3 Protein - metabolism NLRP3 Pharmacology Potassium Potassium - metabolism potassium channel Potassium Channels Potassium Channels, Tandem Pore Domain - metabolism Pyrin protein Receptor mechanisms Therapeutic targets THIK‐1 NLRP3 potassium channel interleukin-1 THIK-1 inflammation inflammasome
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Summary:	The NLRP3 (NLR family, pyrin domain containing 3) 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 (KO) 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 KO 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. Main Points The NLRP3 inflammasome is implicated as a driver of inflammation in neurodegenerative diseases. THIK‐1 regulates ATP‐induced NLRP3 activation in macrophages and microglia. THIK‐1 is a potential target for limiting inflammation in disease.
Bibliography:	Funding information Medical Research Council, Grant/Award Numbers: MR/N013751/1, MR/T016515/1 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Funding information Medical Research Council, Grant/Award Numbers: MR/N013751/1, MR/T016515/1
ISSN:	0894-1491 1098-1136 1098-1136
DOI:	10.1002/glia.24174