Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
Cells. 2023 Mar 10;12(6):868. doi: 10.3390/cells12060868.
In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration.
除了与疾病相关的小胶质细胞 (DAM) 外，具有 MHC-II 和/或 IFN-I 特征的小胶质细胞可能形成与神经退行性变相关的其他致病亚群。然而，这些 MHC-II 和 IFN-I 特征的意义仍然难以捉摸。我们在这里证明，这些小胶质细胞亚群在实验性自身免疫性脑脊髓炎 (EAE) 的神经退行性相关阶段（对应进行性多发性硬化症 [MS]）中，在协调神经毒性 Eomes Th 细胞的神经毒性特性方面发挥内在作用。小胶质细胞在感知异位表达的长散布核元件-1 (L1) 基因后获得 IFN 特征。此外，ORF1 是一种在疾病中枢神经系统 (CNS) 中异常表达的 L1 编码蛋白，在小胶质细胞以 MHC-II 为背景摄取和呈递后，刺激 Eomes Th 细胞。有趣的是，L1 抑制剂的给药显著改善了 EAE 的神经退行性症状，同时减少了 Eomes Th 细胞在中枢神经系统中的积累。总的来说，我们的数据强调了新的小胶质细胞亚群作为免疫介导的神经退行性变中神经炎症中心的关键作用。
