The janus face of astrocytes in multiple sclerosis: Balancing protection and pathology

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system (CNS), predominantly affecting young adults with a notable female predominance. While the pathogenesis of MS involves complex interactions between peripheral immune cells and CNS glia, astrocytes—the most abundant glial cells—play a dual role in disease progression. Traditionally classified into pro-inflammatory A1 and neuroprotective A2 phenotypes, recent single-cell and spatial transcriptomics reveal that human astrocytes exhibit a continuum of states beyond this binary paradigm. In MS, reactive astrocytes contribute to neurotoxicity by disrupting the blood-brain barrier (BBB), promoting glutamate excitotoxicity, and presenting antigens to autoreactive T cells. Conversely, they also support repair through neurotrophic factor release (e.g., BDNF, CNTF) and remyelination. Emerging therapies like dimethyl fumarate (DMF) and fingolimod modulate astrocyte reactivity, targeting oxidative stress and sphingosine-1-phosphate receptors to mitigate neuroinflammation. However, challenges persist in translating murine A1/A2 concepts to human MS, as human astrocytes display heterogeneous, context-dependent responses influenced by regional microenvironments and disease stages. Advanced techniques, including spatial multi-omics, highlight astrocyte-microglia crosstalk and metabolic reprogramming as key drivers of MS pathology. This review synthesizes current evidence on astrocyte heterogeneity, their Janus-faced roles in MS, and the therapeutic potential of astrocyte-targeted strategies, advocating for precision approaches that account for human-specific astrocyte biology. Future research must priorities human-centric biomarkers and dynamic modelling to bridge the gap between experimental findings and clinical applications.