The
cGAS
–
STING
Pathway Drives Astrocyte‐Mediated Demyelination in Multiple Sclerosis Through Clusterin Secretion
Shengfei Hu, Xia Xiao, Xi Cheng, Yiying Huang, Tingting Cui, Shishi Shen, Chunping Cui, Li Xiao, Hanzhang Tan, Wei Qiu, Yipeng Zhao, Rui Li ABSTRACT
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.