Single-Cell Profiling Reveals Mediators of Immune-Vascular Crosstalk in Mouse Models of Relapsing and Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) with heterogeneous clinical courses. While current therapies can modulate the immune system, their efficacy in halting progressive neurodegeneration remains limited, underscoring the need for novel interventions that address both immune and vascular dysfunction. To investigate the mechanisms underlying these processes, we employed the myelin oligodendrocyte glycoprotein (MOG₃₅–₅₅)-induced experimental autoimmune encephalomyelitis (EAE) model, utilizing C57BL/6 mice, which develop a relapsing-remitting MS-like course, and NOD/ShiLtJ mice, which exhibit a secondary-progressive MS-like course. We performed single-cell RNA sequencing (scRNA-seq) on lumbar spinal cord tissues from these EAE models at the disease peak. Our analysis revealed distinct, cell-type-specific transcriptomic landscapes associated with relapsing and progressive pathologies. We identified critical mediators of immune-vascular crosstalk that were dysregulated across both disease phases, pinpointing conserved pathways and cell populations involved in disease perpetuation. Functional validation confirmed that targeting these key pathways can suppress pro-inflammatory immune cell activity, restore vascular integrity, and ameliorate clinical symptoms in both EAE models. This study provides a high-resolution resource of the immune and vascular interactions in relapsing and progressive MS models. Our findings uncover novel mechanisms sustaining neuroinflammation and highlight promising therapeutic targets for modulating both relapsing and progressive forms of MS.