Neuropilins in Multiple Sclerosis: Dual Roles of NRP-1 in Neuroinflammation and Neuroprotection.

Neuropilins (NRPs), particularly NRP-1, are multifunctional co-receptors involved in neuroinflammatory and neuroprotective processes. Altered NRP expression has been observed in multiple sclerosis (MS) lesions and peripheral circulation, suggesting early involvement in disease progression. This review addresses the dual role of NRPs in MS and experimental autoimmune encephalomyelitis (EAE), emphasizing expression patterns, signaling pathways, and therapeutic interventions. NRP-1 is expressed by endothelial cells, microglia, and macrophages, while Sema3A, a key ligand, is produced by reactive astrocytes and contributes to a non-regenerative microenvironment. NRP-1 is involved in regulating blood-brain barrier (BBB) integrity, contributes to leukocyte trafficking, and modulates inflammatory signaling via the IFN-γ-STAT1-CXCL10 axis. In EAE, endothelial-specific NRP-1 deletion reduces disease severity, demyelination, and immune infiltration. Immunologically, NRP-1 governs interactions among T cells, dendritic cells, and macrophages, facilitating regulatory T cell (Treg) function and peripheral tolerance. Trogocytosis-mediated NRP-1 transfer from dendritic cells to T cells and polysialylated NRP-2 on dendritic cells further influence immune modulation. Tuftsin, a tetrapeptide targeting NRP-1, promotes anti-inflammatory microglial polarization and Treg activation, improving EAE outcomes. Therapeutic interventions, such as Bu-Shen-Yi-Sui Capsule (BSYSC), FTX-101 (a Sema3A-NRP-1 inhibitor), and tuftsin restore BBB function, reduce inflammation, enhance remyelination, and improve clinical scores. NRP-1 signaling thus exhibits context-dependent dual roles: promoting inflammatory cascades while enabling neuroprotection through regulatory immune networks and oligodendrocyte precursor cell support, highlighting NRP-1 as a therapeutic target in MS.