Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.
Cell Death Dis. 2023 Jan 12;14(1):16. doi: 10.1038/s41419-023-05551-3.
In multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, both resident microglia and infiltrating macrophages contribute to demyelination as well as spontaneous remyelination. Nevertheless, the specific roles of microglia versus macrophages are unknown. We investigated the influence of microglia in EAE using the colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX5622, to deplete microglial population and Ccr2 fms mice, to distinguish blood-derived macrophages from microglia. PLX5622 treatment depleted microglia and meningeal macrophages, and provoked a massive infiltration of CCR2 macrophages into demyelinating lesions and spinal cord parenchyma, albeit it did not alter EAE chronic phase. In contrast, microglia and meningeal macrophages depletion reduced the expression of major histocompatibility complex II and CD80 co-stimulatory molecule in dendritic cells, macrophages and microglia. In addition, it diminished T cell reactivation and proliferation in the spinal cord parenchyma, inducing a significant delay in EAE onset. Altogether, these data point to a specific role of CNS microglia and meningeal macrophages in antigen presentation and T cell reactivation at initial stages of EAE.
在多发性硬化症和实验性自身免疫性脑脊髓炎 (EAE) 模型中，常驻小胶质细胞和浸润巨噬细胞均有助于脱髓鞘以及自发的髓鞘再生。然而，小胶质细胞与巨噬细胞的具体作用尚不清楚。我们使用集落刺激因子 1 受体 (CSF-1R) 抑制剂 PLX5622 来研究小胶质细胞在 EAE 中的影响，以耗尽小胶质细胞群体，并使用 Ccr2 fms 小鼠来区分血液来源的巨噬细胞和小胶质细胞。PLX5622 处理耗尽了小胶质细胞和脑膜巨噬细胞，并引发 CCR2 巨噬细胞大量浸润脱髓鞘病变和脊髓实质，但并未改变 EAE 的慢性期。相比之下，小胶质细胞和脑膜巨噬细胞的耗竭减少了树突状细胞、巨噬细胞和小胶质细胞中主要组织相容性复合体 II 和 CD80 共刺激分子的表达。此外，它还减少了脊髓实质中 T 细胞的再激活和增殖，导致 EAE 发作明显延迟。总之，这些数据表明中枢神经系统小胶质细胞和脑膜巨噬细胞在 EAE 初始阶段的抗原呈递和 T 细胞再激活中具有特定作用。
