The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions

Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursor cells (OPCs), peaks in immature oligodendrocytes, and is subsequently downregulated to allow terminal maturation. Under neuroinflammatory conditions, GPR17 expression persists, suggesting a possible role in impaired oligodendrocyte maturation and defective myelination. Here, we tested whether receptor modulation by the selective GPR17 agonist Galinex (GAL) can support oligodendrocyte maturation under inflammatory conditions.

Differentiating oligodendroglial cultures were exposed to a pro-inflammatory cytokine cocktail composed of TNFα, IL-1β, and IFNγ. We first identified a subtoxic inflammatory condition, defined as cytokine exposure that did not cause overt loss of cell viability, and assessed oligodendrocyte maturation, myelin-associated marker expression, GPR17 expression, and transcriptional remodelling. Publicly available transcriptomic signatures from neuroinflammatory mouse models and human Alzheimer's disease and multiple sclerosis brains were used for cross-comparison. The effect of GAL was then evaluated by molecular, morphological, and functional readouts, including a synthetic nanofiber myelination assay.

Subtoxic cytokine exposure consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomic analysis revealed coordinated remodelling of pathways related to protein synthesis and proteostasis, mitochondrial metabolism, lipid homeostasis, and inflammatory/immunogenic-like responses, together with senescence- and DNA damage-associated features. Cross-comparison with disease-associated transcriptomic signatures showed significant overlap with neuroinflammatory modules, supporting the relevance of the inflammatory pathways engaged in our model. GAL treatment partially restored terminal maturation-associated features and oligodendrocyte morphology. Moreover, in the nanofiber assay, GAL significantly increased the length of MBP-positive segments compared with CTK-treated cells, suggesting improved wrapping/myelination-like capacity after inflammatory challenge.

Together, this study establishes a controlled in vitro model linking inflammatory cytokine exposure, disease-associated transcriptional alterations, and impaired oligodendrocyte differentiation. Our findings indicate that pharmacological modulation of GPR17 can promote oligodendrocyte maturation and wrapping features under non-permissive inflammatory conditions. This strategy should be considered as an oligodendroglial-directed approach that may complement anti-inflammatory or immunomodulatory interventions.