RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis.

Oligodendroglial lineage cells (OLCs) are critical for neuronal support functions, including myelination and remyelination. Emerging evidence reveals their active roles in neuroinflammation, particularly in conditions like Multiple Sclerosis (MS). This study explores the inflammatory translatome of OLCs during the early onset of experimental autoimmune encephalomyelitis (EAE), an established MS model. Using RiboTag-based RNA sequencing in genetically modified Olig2-Cre RiboTag mice, we identified 1,556 upregulated and 683 downregulated genes in EAE OLCs. Enrichment analysis indicated heightened immune-related pathways, such as cytokine signaling, interferon responses, and antigen presentation, while downregulated genes were linked to neuronal development and myelination. Notably, OLCs expressed cytokines/chemokines, and their receptor, highlighting their active involvement in neuroinflammatory signaling. Functional studies demonstrated that interferon-gamma (IFN-γ) signaling in OLCs exacerbates EAE pathology by enhancing antigen presentation and chemokine production, whereas interferon-beta (IFN-β) signaling showed minimal impact. These findings provide novel insights into the inflammatory role of OLCs in EAE and suggest therapeutic potential in targeting OLC-mediated neuroinflammation for MS and related disorders.