Desu Haritha L, Thougaard Estrid, Carney Brianna N, Illiano Placido, Plastini Melanie J, Florimon Yoleinny, Mini Antonella, Guastucci Chelsea, Kang Brian, Lee Jae K, Lambertsen Kate L, Brambilla Roberta
The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense M, Denmark.
Brain Behav Immun. 2025 Jan;123:81-98. doi: 10.1016/j.bbi.2024.09.002. Epub 2024 Sep 5.
Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In Pdgfrα:Tnfrsf1b:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, Pdgfrα:Tnfrsf1b:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated "foamy" phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性退行性疾病，其特征为炎症、脱髓鞘和进行性神经变性。这些过程，再加上少突胶质前体细胞（OPC）启动的修复性髓鞘再生失败，导致不可逆转的神经功能损害。细胞因子肿瘤坏死因子（TNF）通过在神经胶质细胞中激活其同源受体TNFR2参与中枢神经系统修复。在此，我们证明了TNFR2在脱髓鞘疾病期间体内调节OPC功能中的重要作用，并且OPC中表达的TNFR2调节OPC与小胶质细胞的相互作用。在OPC中选择性缺失TNFR2的Pdgfrα:Tnfrsf1b:Eyfp小鼠中，我们观察到实验性自身免疫性脑脊髓炎（EAE）的发病更早且疾病峰值更高。这与脊髓中免疫细胞浸润加速和小胶质细胞活化增加有关。同样，在铜螯合剂诱导脱髓鞘后，Pdgfrα:Tnfrsf1b:Eyfp小鼠胼胝体中的小胶质细胞反应性与对照小鼠相比迅速增加且增强，随后成熟髓鞘形成少突胶质细胞（OL）数量长期减少。结合EAE和铜螯合剂模型，我们发现TNFR2在OPC分化中不具有细胞自主作用，但可能对新形成的成熟OL的存活很重要。最后，使用体外方法，我们证明当与富含髓磷脂的脊髓匀浆孵育时，Tnfrsf1b缺失的OPC释放的因子驱使小胶质细胞发展出加剧的“泡沫状”表型，异常增加溶酶体脂质积累。总之，我们的数据表明OPC中的TNFR2信号通过抑制其免疫炎症激活和抑制神经毒性小胶质细胞反应性而具有保护作用。这表明增强TNFR2激活或其下游级联反应可能是恢复神经免疫和脱髓鞘疾病中OPC修复能力的有效策略。
