Chloride Homeostasis Regulates cGAS-STING Signaling

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 23-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. HighlightsO_LIChloride dysregulation attenuates cGAS-STING signaling in a lysosome-independent manner. C_LIO_LIChloride dysregulation attenuates intracellular 23-cGAMP production. C_LIO_LIChloride dysregulation inhibits STING polymerization and STING-to-IRF3 signaling. C_LIO_LIChloride channel blockers suppress NPC1 deficiency-induced, hyper-activated STING signaling. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/588475v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@cf8b59org.highwire.dtl.DTLVardef@1c5859aorg.highwire.dtl.DTLVardef@c6622borg.highwire.dtl.DTLVardef@571646_HPS_FORMAT_FIGEXP M_FIG C_FIG