Interferon-β and FTY720 ameliorate progressive CNS inflammation via SOCS1-associated astrocyte signaling.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by initially relapsing-remitting neurological deficits followed by progressive and largely irreversible disability driven by glial and neuronal pathology behind an increasingly restrictive blood–brain barrier, limiting access of peripherally applied therapeutics. Here, we show that combining sphingosine-1-phosphate receptor (S1PR) modulation with CNS-penetrant intranasal interferon-β (nIFN-β) enhances therapeutic effects relative to FTY720 alone in a chronic progressive EAE model. Combined treatment reduces CNS-infiltrating immune cells, decreases pro-inflammatory cytokine production, and augments protective glial programs in vivo, as well as in human astrocyte and microglial cell lines. Transcriptomic and perturbation analyses implicate SOCS1-associated signaling as a modulatory component of treatment-induced glial responses. Together, these findings support further investigation of combinatorial FTY720/nIFN-β strategies targeting CNS-intrinsic inflammatory pathways in progressive MS.