Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis.
Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis.
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WNK1对氯化物的感知调节NLRP3炎性体的激活和焦亡。
DOI：
10.1038/s41467-021-24784-4
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发表时间：
2021-07-27
影响因子：
16.6
通讯作者：
Alnemri ES
中科院分区：
文献类型：
--
作者：
Mayes-Hopfinger L;Enache A;Xie J;Huang CL;Köchl R;Tybulewicz VLJ;Fernandes-Alnemri T;Alnemri ES
NLRP3炎症小体介导促炎细胞因子的产生并引发炎症细胞死亡。尽管NLRP3对先天免疫至关重要，但异常的NLRP3炎性体激活会导致多种炎症性疾病。了解控制NLRP3激活的途径将有助于制定治疗这些疾病的策略。在这里，我们确定WNK1是NLRP3炎症小体的负调节因子。与对照巨噬细胞相比，缺乏WNK1蛋白或激酶活性的巨噬细胞增加了NLRP3的激活和焦亡。与对照组小鼠相比，巨噬细胞条件敲除WNK1的小鼠在NLRP3刺激下增加了IL-1β的产生。在机制上，WNK1通过在NLRP3激活过程中平衡细胞内Cl -和K+浓度来调节NLRP3的激活。总的来说，这项工作表明WNK1途径在抑制NLRP3激活方面具有关键作用，并表明药物抑制该途径治疗高血压可能具有负面的临床意义。丝氨酸/苏氨酸激酶WNK1是氯外排的抑制剂。本文作者表明，这种抑制是一种负性调节巨噬细胞NLRP3炎性体激活的手段，导致炎症反应减少。
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. The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.
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影响因子：
16.6
作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
通讯作者：
Brough D
caspase-8脚手架函数和MLKL调节TLR3下游的NLRP3炎性体激活。
影响因子：
16.6
作者：
Kang, Seokwon;Fernandes-Alnemri, Teresa;Rogers, Corey;Mayes, Lindsey;Wang, Ying;Dillon, Christopher;Roback, Linda;Kaiser, William;Oberst, Andrew;Sagara, Junji;Fitzgerald, Katherine A.;Green, Douglas R.;Zhang, Jianke;Mocarski, Edward S.;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
影响因子：
4.9
作者：
Evans PL;Prior JA;Belcher J;Mallen CD;Hay CA;Roddy E
通讯作者：
Roddy E
影响因子：
4.8
作者：
Juliana, Christine;Fernandes-Alnemri, Teresa;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
DOI：
10.1161/hypertensionaha.109.129171
发表时间：
2009-08
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Ellison DH;Loffing J
通讯作者：
Loffing J