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

作者：Qi Wang, Taida Huang, Zihan Zheng, Yixun Su, Zhonghao Wu, Cong Zeng, Guangdan Yu, Yang Liu, Xiaorui Wang, Hui Li, Xiaoying Chen, Zhuoxu Jiang, Jinyu Zhang, Yuan Zhuang, Yi Tian, Qingwu Yang, Alexei Verkhratsky, Ying Wan, Chenju Yi, Jianqin Niu · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adn9980 · 被引用次数：27 · 研究领域：Multiple Sclerosis Research Studies、Neuroinflammation and Neurodegeneration Mechanisms、Immune Cell Function and Interaction

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 infiltrat...