The cGAS – STING Pathway Drives Astrocyte‐Mediated Demyelination in Multiple Sclerosis Through Clusterin Secretion

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BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory disorder characterized by oligodendrocyte injury and demyelination. The disease progresses from peripheral immune attacks to compartmentalized central nervous system (CNS) inflammation, culminating in irreversible neurodegeneration. Although current immunotherapies suppress peripheral relapses, they inadequately address compartmentalized CNS inflammation and progressive neurodegeneration. METHODS: We reanalyzed published single-nucleus RNA-seq datasets from human MS lesions. Primary astrocytes, oligodendrocytes, and organotypic cultures were used for in vitro studies. Outcomes were assessed by immunofluorescence, Western blot, qRT-PCR, RNA-seq, cell viability assay, and behavioral scoring. The STING inhibitor H-151 was administered in preventive and therapeutic paradigms. RESULTS: Single-nucleus RNA-seq showed inflammatory astrocytes accumulate preferentially at chronic active lesion edges in MS. These astrocytes exhibited STING pathway activation, coinciding with elevated DNA concentrations in cerebrospinal fluid. Mechanistically, DNA synergized with pro-inflammatory cytokines to trigger astrocytic STING signaling, driving Clusterin (CLU) secretion that directly induced oligodendrocyte apoptosis and demyelination. Pharmacological inhibition of STING with H-151 prevented and ameliorated established clinical deficits in experimental autoimmune encephalomyelitis mice. CONCLUSION: DNA elevation in inflammatory microenvironments activates the astrocytic STING-CLU axis to promote disease pathogenesis, validating STING targeting as a treatment strategy for MS.

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