The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.
The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.
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DOI：
10.1016/j.phrs.2023.107016
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发表时间：
2023-11
影响因子：
9.3
通讯作者：
Xiaoyan Wu;Xin Yi;Boxin Zhao;Yuanxing Zhi;Ziwei Xu;Ying Cao;Xiong Cao;Jianxin Pang;Ken Kin Lam Yung;Shiqing Zhang;Shuwen Liu;Pingzheng Zhou
中科院分区：
文献类型：
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作者：
Xiaoyan Wu;Xin Yi;Boxin Zhao;Yuanxing Zhi;Ziwei Xu;Ying Cao;Xiong Cao;Jianxin Pang;Ken Kin Lam Yung;Shiqing Zhang;Shuwen Liu;Pingzheng Zhou
NLRP3炎性小体是一种与无菌和病原体依赖性炎症相关的超分子复合物，其过度激活是许多疾病的基础。据报道，离子通量干扰和细胞体积调节都介导了NLRP3炎性体的激活，但潜在的协调信号仍未完全阐明。由LRRC8蛋白形成的体积调节阴离子通道（VRAC）是细胞肿胀反应中通过渗透氯离子和有机渗透物来控制细胞体积的重要组成部分。我们现在证明，Lrrc8a， VRAC的重要组成部分，在典型NLRP3炎性体激活中起着核心和特定的作用。此外，对于需要K+外排的NLRP3刺激，VRAC作用于K+外排的下游。机械地，我们的数据表明，VRAC调节itacon酸外排和受损线粒体的产生，以激活NLRP3炎性体。进一步的体内实验表明，髓细胞缺乏lrrc8a的小鼠可以免受脂多糖（LPS）诱导的内毒素休克。综上所述，本研究通过调节线粒体对巨噬细胞活化的适应，确定了VRAC是NLRP3炎症小体和先天免疫的关键调节因子，并强调了VRAC是治疗NLRP3炎症小体和衣康酸相关疾病的潜在药物靶点。
The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+efflux for NLRP3 stimuli that require K+efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice withLrrc8adeficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases.