Activation status of astrocytes drives the MS/NMOSD therapeutic paradox: Insights from IFNAR1 signaling.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease of the central nervous system (CNS) that, despite overlapping phenotypic features with multiple sclerosis (MS), manifests with more severe clinical outcomes. The defining pathogenic driver of NMOSD is the aquaporin-4 (AQP4) autoantibody, which induces astrocytic injury via complement-dependent cytotoxicity (CDC). MS is predominantly managed with disease-modifying therapies (DMTs) such as interferon-beta (IFN-β) to reduce relapse rates. However, these therapies are often ineffective or even detrimental in NMOSD. Our findings demonstrate that while IFN-β mitigates experimental autoimmune encephalomyelitis (EAE), it exacerbates NMOSD-like astrocytopathy. Deleting IFNAR1 counteracts this effect by selectively enhancing astrocyte activation without altering other CNS cells. Subsequently, we characterized multiple MS therapeutics that paradoxically worsen NMOSD-like pathology, whereas agents promoting astrocytic activation confer protection. Collectively, we establish a framework for astrocyte-centered drug screening and underscore the therapeutic potential of targeting astrocytes in NMOSD, connecting fundamental disease mechanisms to clinical applications.