Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Nat Med. 2013 May;19(5):595-602. doi: 10.1038/nm.3111. Epub 2013 Apr 21.
Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor-associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.
小胶质细胞在多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的发病机制中起着至关重要的作用。在这里，我们表明 E3 泛素连接酶 Peli1 在小胶质细胞中大量表达，并在 EAE 诱导过程中促进小胶质细胞的激活。Peli1 介导小胶质细胞中趋化因子和促炎细胞因子的诱导，从而促进 T 细胞进入中枢神经系统。尽管 Peli1 缺失小鼠在外周淋巴器官中能够诱导炎症性 T 细胞，但它们的 EAE 严重程度降低。值得注意的是，Peli1 通过促进肿瘤坏死因子受体相关因子 3（Traf3）的降解来调节 Toll 样受体（TLR）信号通路，Traf3 是丝裂原活化蛋白激酶（MAPK）激活和基因诱导的有效抑制剂。在 Peli1 缺失小鼠中 EAE 诱导后，Traf3 的缺失恢复了小胶质细胞的激活和中枢神经系统炎症。这些发现确立了 Peli1 作为自身免疫性神经炎症的小胶质细胞特异性介质，并提示了 Peli1 功能的一个以前未知的信号机制。
