Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis

Abstract

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 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 brain through CC-chemokine ligand 4 (CCL4), whilst OPCs cooperate with Th1 cells inducing transformation 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.

Unlocking the Potential: immune functions of oligodendrocyte precursor cells

“…This cytokine also attracts CD8 + T cells to MS lesions, resulting in OPC death through the activation of caspase cascades via the Fas/FasL and perforin/granzyme pathways ( 24 ) ( Figure 2 ). Furthermore, a recent study observed that OPCs, along with Th1 cells, activate a subset of macrophages, leading them to become cytotoxic and subsequently induce OPC apoptosis ( 26 ). It seems that, initiated by unknown reason, OPC-expressed CCL4 starts to attract Th1 cells, and two together further recruit macrophages.…”

“…Under pathological conditions, OPCs become hypertrophic ( 22 , 23 ) ( Figures 1B–E ) and release and/or respond to cytokines ( 17 , 24 , 25 ). In multiple sclerosis (MS), OPCs also enhance the expression of MHC I and II molecules and interact with immune cells ( 24 , 26 ). All of these studies provide strong evidence of the immune function of OPC.…”