Oligodendroglial precursor cells modulate immune response and early demyelination in a murine model of multiple sclerosis

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Abstract
Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis (EAE) in Pdgfra CreER ;Apc fl/fl and Olig2 Cre ;Apc fl/fl mice. These mice have overactivated Wnt signaling in oligodendrocyte precursor cells (OPCs) because of a conditional knockout of the pathway repressor adenomatous polyposis coli (APC). Pdgfra CreER ;Apc fl/fl EAE mice exhibited increased expression of markers for Wnt activation such as Axis inhibition protein 2 (AXIN2) and Wnt inhibitory factor 1 (WIF1) in OPCs and showed exacerbated EAE progression in both the spinal cord and the brain. Genetic or antibody-mediated ablation of CC-chemokine ligand 4 (CCL4) prevented infiltration of CD4 + T cells and arrested disease progression in these mice. A characterization of CNS (central nervous system) immune cell clusters identified an augmented subpopulation of NK1.1 + CD11b + Gr-1 + cytotoxic macrophages in Pdgfra CreER ;Apc fl/fl EAE mice. Microinjection of this subpopulation of macrophages into the brains of wild-type C57/B6J mice was sufficient to induce demyelination. Ablation of CD4 + T cells prevented the effects of Wnt overactivation on demyelination and immune cell infiltration. Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency–approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.

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