RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis 2748

Abstract Description Oligodendroglial lineage cells (OLCs) are critical for myelination, remyelination and neuronal metabolic support, but recent evidence suggests they also play active roles in neuroinflammation. This study aimed to identify the inflammatory translatome of OLCs at the onset of experimental autoimmune encephalomyelitis (EAE), a model for Multiple Sclerosis (MS), using RiboTag-based RNA sequencing. We crossed RiboTag mice with Olig2-Cre mice to obtain mice strain specific expression of HA-tagged ribosomal protein Rpl22 in OLCs, facilitating the isolation of ribosome-associated mRNA from these cells for sequencing by using HA beads. Compared to controls, 1,556 genes were upregulated, and 683 downregulated in EAE OLCs. Gene enrichment revealed elevated immune-related pathways, including cytokine signaling, interferon responses, and antigen presentation. Conversely, downregulated genes were involved in myelination and neuronal development. Notably, we found significant expression of cytokine receptors, chemokine receptors, and toll-like receptors on OLCs. Further, we investigated the role of IFNGR and IFNAR in EAE pathogenesis. IFN-γ signaling in OLCs exacerbated EAE pathology by enhancing antigen processing, presentation, and chemokine production (e.g., Ccl2, Ccl7), while IFN-β signaling appeared less critical. These findings highlight the inflammatory role of OLCs in EAE, suggesting OLCs as a potential therapeutic target for mitigating neuroinflammation in MS and related disorders. Funding Sources Startup fund from the Department of pathology at the University of IOWA, NIH R01 NS104164, and R21AG076895 to Z.K. Topic Categories Basic Autoimmunity (BA)