Oligodendroglial precursors orchestrate immune cellular network instigating multiple sclerosis

The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of the Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+ T-helper 1 (Th1) cells into the spinal cord and the brain through CC-chemokine ligand 4 (CCL4). Th1 cells cooperate with OPCs inducing subpopulation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology