The proinflammatory
cytokine IFN-γ, which is chronically elevated in
multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the
transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of
heparan sulfate proteoglycans in the modulation of IFN-γ signaling following
demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord
demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNγR1 (Ifngr1) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that
PI-88, a
heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly,
heparanase modulation by
PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and
demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive
astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death.
Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.SIGNIFICANCE STATEMENT The failure of remyelination in
multiple sclerosis contributes to
neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory
cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following
demyelination.
Heparan sulfate is a highly structured sulfated
carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic
interferon-γ can be blocked by modulation of the heparanome following
demyelination using either a heparan mimetic or by treatment with
heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in
demyelinating disease.