Nervous System-Specific SARM1 Knockout Attenuates Optic Neuritis in a Multiple Sclerosis Mouse Model

In optic neuritis, a complication of multiple sclerosis (MS), the main pathological manifestations are autoimmune-mediated inflammatory infiltration, myelin loss, and axonal damage. We generated conditional SARM1 cKO mice in the nervous system and performed MOG_35-55-induced experimental autoimmune encephalomyelitis (EAE). Clinical scores were monitored through day 21, and optomotor responses were assessed. Retinal and optic nerve pathology was evaluated by histology, immunofluorescence, and transmission electron microscopy. SARM1 expression was examined by immunostaining, RNAscope, and Western blotting. Bulk RNA sequencing, RT-qPCR, and p-STAT3/GFAP immunostaining were used to assess transcriptional changes and astrocytic STAT3 signaling. Compared with SARM1^f/f EAE mice, SARM1^Nestin-CKO EAE mice showed lower EAE clinical severity, reduced inflammatory and glial responses, and less severe axonal and myelin pathology in the optic nerve. Neural-lineage SARM1 deletion was also associated with lower astrocyte-reactivity-related transcriptional signatures and reduced nuclear p-STAT3 signal in GFAP-positive cells. Neural-lineage SARM1 contributes to EAE-associated optic-nerve pathology. Its deletion is associated with reduced astrocyte reactivity and STAT3 phosphorylation.