Morse Jared, Wang Danna, Mei Serena, Whitham Danielle, Hladun Colby, Darie Costel C, Sintim Herman O, Wang Modi, Leung KaHo
Department of Chemistry & Biomolecular Science, Clarkson University, NY, 13676, United States.
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
bioRxiv. 2024 Apr 9:2024.04.08.588475. doi: 10.1101/2024.04.08.588475.
The cGAS-STING signaling pathway has emerged as a key mediator of inflammation. However, the roles of chloride homeostasis on this pathway are unclear. Here, we uncovered a correlation between chloride homeostasis and cGAS-STING signaling. We found that dysregulation of chloride homeostasis attenuates cGAS-STING signaling in a lysosome-independent manner. Treating immune cells with chloride channel inhibitors attenuated 2'3'-cGAMP production by cGAS and also suppressed STING polymerization, leading to reduced cytokine production. We also demonstrate that non-selective chloride channel blockers can suppress the NPC1 deficiency-induced, hyper-activated STING signaling in skin fibroblasts derived from Niemann Pick disease type C (NPC) patients. Our findings reveal that chloride homeostasis majorly affects cGAS-STING pathway and suggest a provocative strategy to dampen STING-mediated inflammation via targeting chloride channels.
环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）信号通路已成为炎症的关键介质。然而，氯离子稳态在此信号通路上的作用尚不清楚。在此，我们揭示了氯离子稳态与cGAS-STING信号之间的关联。我们发现，氯离子稳态失调以不依赖溶酶体的方式减弱cGAS-STING信号。用氯离子通道抑制剂处理免疫细胞会减弱cGAS产生2'3'-环鸟苷酸-腺苷酸（2'3'-cGAMP）的能力，还会抑制STING聚合，从而导致细胞因子产生减少。我们还证明，非选择性氯离子通道阻滞剂可抑制来自C型尼曼匹克病（NPC）患者的皮肤成纤维细胞中NPC1缺陷诱导的过度激活的STING信号。我们的研究结果表明，氯离子稳态主要影响cGAS-STING信号通路，并提出了一种通过靶向氯离子通道来减轻STING介导的炎症的激发性策略。
