The two pore potassium channel THIK-1 regulates NLRP3 inflammasome activation.
The two pore potassium channel THIK-1 regulates NLRP3 inflammasome activation.
复制标题
两孔钾通道THIK-1调节NLRP 3炎性体活化。
作者：
NLRP 3（NLR家族，含pyrin结构域3）炎性体是一种多蛋白复合物，负责激活caspase-1，随后裂解和激活强效促炎细胞因子IL-1β和IL-18，以及pyroptotic细胞死亡。NLRP 3被认为是一系列疾病中炎症的驱动因素，包括神经退行性疾病、2型糖尿病和动脉粥样硬化。通常报道的促进NLRP 3炎性小体活化的机制是钾离子（K+）流出穿过质膜。参与NLRP 3激活的K+通道的鉴定仍然不完整。在这里，我们研究了K+通道THIK-1在NLRP 3激活中的作用。使用药理学抑制剂和来自THIK-1敲除（KO）小鼠的细胞来评估THIK-1对体外巨噬细胞NLRP 3活化的贡献。THIK-1的药理学抑制抑制了响应NLRP 3激动剂的小鼠骨髓源性巨噬细胞（BMDM）、混合神经胶质细胞和小神经胶质细胞的caspase-1活化和IL-1β释放。类似地，来自THIK-1 KO小鼠的BMDM和小胶质细胞响应于ATP激活P2 X7受体而减少了NLRP 3依赖性IL-1β释放。总的来说，这些数据表明THIK-1是响应ATP的NLRP 3炎性体活化的调节剂，并将THIK-1确定为炎性疾病的潜在治疗靶点。NLRP 3炎性体被认为是神经退行性疾病中炎症的驱动因素。THIK-1调节巨噬细胞和小胶质细胞中ATP诱导的NLRP 3活化。THIK-1是限制疾病炎症的潜在靶点。
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. 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.
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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
影响因子：
3.4
作者：
Bobak, Nicole;Bittner, Stefan;Sukhorukov, Vladimir L.
通讯作者：
Sukhorukov, Vladimir L.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
5.4
作者：
Hornung, Veit;Latz, Eicke
通讯作者：
Latz, Eicke
影响因子：
64.8
作者：
Ding, Jingjin;Wang, Kun;Shao, Feng
通讯作者：
Shao, Feng