Article ; Online: Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis.
2021 Volume 12, Issue 1, Page(s) 4546
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 ... ...
| 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 |
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| MeSH term(s) | 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 ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neutrophils/drug effects ; Neutrophils/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 ; Mice |
| Chemical Substances | Chlorides ; Imidazoles ; Inflammasomes ; Interleukin-1beta ; Lipopolysaccharides ; NLR Family, Pyrin Domain-Containing 3 Protein ; Pyrrolidines ; WNK463 ; Tamoxifen (094ZI81Y45) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Stk39 protein, mouse (EC 2.7.1.-) ; OXSR1 protein, mouse (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; WNK Lysine-Deficient Protein Kinase 1 (EC 2.7.11.1) ; Wnk1 protein, mouse (EC 2.7.11.1) ; Caspase 1 (EC 3.4.22.36) ; Potassium (RWP5GA015D) |
| Language | English |
| Publishing date | 2021-07-27 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-021-24784-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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