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Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis

Research output: Contribution to journalArticlepeer-review

Lindsey Mayes-Hopfinger, Aura Enache, Jian Xie, Chou Long Huang, Robert Köchl, Victor L.J. Tybulewicz, Teresa Fernandes-Alnemri, Emad S. Alnemri

Original languageEnglish
Article number4546
JournalNature Communications
Volume12
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (NIH) grants AR055398, AR074564 and AR078440 (ESA), the National Institute of Diabetes and Digestive and Kidney Diseases, NIH grant DK111542 (C-LH) and the Cancer Research UK, the UK Medical Research Council and the Wellcome Trust grant FC001194 (VLJT). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Abstract

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.

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