RiboTag-based RNA profiling uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis: implications for pathogenesis.

Oligodendroglial lineage cells (OLCs) are essential 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 during the onset of experimental autoimmune encephalomyelitis (EAE), a widely used model for Multiple Sclerosis (MS), using RiboTag-based RNA sequencing. We crossed RiboTag mice with Olig2-Cre mice to obtain strain-specific expression of HA-tagged ribosomal protein Rpl22 in OLCs, enabling 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 were downregulated in EAE OLCs. Gene enrichment revealed elevated immune-related pathways, including cytokine signaling, interferon responses and antigen presentation, whereas downregulated genes were associated with myelination and neuronal development. Notably, significant expression of cytokines/chemokines and their receptors was detected in OLCs. Further investigations focused on the role of IFNGR and IFNAR in EAE pathogenesis. IFN-γ signaling in OLCs exacerbated EAE pathogenesis by enhancing antigen processing, presentation, and chemokine production (e.g., Ccl2, Ccl7). In contrast, 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.