Chloride Homeostasis Regulates cGAS-STING Signaling

Abstract

SummaryThe 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.HighlightsChloride dysregulation attenuates cGAS-STING signaling in a lysosome-independent manner.Chloride dysregulation attenuates intracellular 2’3’-cGAMP production.Chloride dysregulation inhibits STING polymerization and STING-to-IRF3 signaling.Chloride channel blockers suppress NPC1 deficiency-induced, hyper-activated STING signaling.Graphical abstract