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

Area of Science:

• Neuroimmunology
• Neuroinflammation
• Neurodegeneration

Background:

• Multiple sclerosis (MS) is a chronic neuroinflammatory disease causing oligodendrocyte injury, demyelination, and neurodegeneration.
• Current MS therapies fail to effectively manage central nervous system (CNS) inflammation and progressive neurodegeneration.

Purpose of the Study:

• Investigate the mechanisms driving CNS inflammation and neurodegeneration in MS.
• Identify potential therapeutic targets for MS.

Main Methods:

• Analysis of single-nucleus RNA-seq data from human MS lesions.
• In vitro studies using primary astrocytes and oligodendrocytes.
• Assessment of outcomes via immunofluorescence, Western blot, qRT-PCR, RNA-seq, cell viability assays, and behavioral scoring.
• Administration of the STING inhibitor H-151 in mouse models of MS.

Main Results:

• Inflammatory astrocytes with activated STING signaling accumulate at chronic active MS lesion edges.
• Elevated cerebrospinal fluid DNA synergizes with cytokines to activate astrocytic STING.
• Activated STING signaling drives Clusterin (CLU) secretion, inducing oligodendrocyte apoptosis and demyelination.
• STING inhibition with H-151 ameliorated clinical deficits in experimental autoimmune encephalomyelitis mice.

Conclusions:

• Elevated DNA in inflammatory MS microenvironments activates the astrocytic STING-CLU axis, promoting disease pathogenesis.
• Targeting the STING pathway represents a viable therapeutic strategy for MS.