Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis

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

doi:10.1038/s41467-021-24784-4

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Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis

Journal article

Open access

Peer reviewed

Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis

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

Nature communications, Vol.12(1), pp.4546-4546

07/27/2021

DOI: 10.1038/s41467-021-24784-4

PMCID: PMC8316491

PMID: 34315884

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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.

Animals

Caspase 1 - metabolism

Chlorides - metabolism

Female

Imidazoles - pharmacology

Immunity, Innate - drug effects

Inflammasomes - metabolism

Interleukin-1beta - metabolism

L-Lactate Dehydrogenase - metabolism

Lipopolysaccharides - pharmacology

Macrophages - drug effects

Macrophages - metabolism

Male

Mice, Inbred C57BL

Models, Biological

Neutrophils - drug effects

Neutrophils - metabolism

NLR Family, Pyrin Domain-Containing 3 Protein - metabolism

Potassium - metabolism

Protein Serine-Threonine Kinases - metabolism

Pyroptosis - drug effects

Pyrrolidines - pharmacology

Tamoxifen - pharmacology

WNK Lysine-Deficient Protein Kinase 1 - antagonists & inhibitors

WNK Lysine-Deficient Protein Kinase 1 - metabolism

Details

Title: Subtitle: Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis
Creators: Lindsey Mayes-Hopfinger - Thomas Jefferson University
Aura Enache - Thomas Jefferson University
Jian Xie - University of Iowa
Chou-Long Huang - University of Iowa
Robert Köchl - King's College London
Victor L J Tybulewicz - Imperial College London
Teresa Fernandes-Alnemri - Thomas Jefferson University
Emad S Alnemri - Thomas Jefferson University
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), pp.4546-4546
DOI: 10.1038/s41467-021-24784-4
PMID: 34315884
PMCID: PMC8316491
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: FC001194 / Wellcome Trust Wellcome Trust Medical Research Council R01 AR078440 / NIAMS NIH HHS FC001194 / Arthritis Research UK R01 DK111542 / NIDDK NIH HHS FC001194 / Cancer Research UK R01 AR055398 / NIAMS NIH HHS R01 AR074564 / NIAMS NIH HHS
Language: English
Date published: 07/27/2021
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984360156002771

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