Department of Neuropathology, University of Freiburg, Freiburg, Germany.
Nat Neurosci. 2011 Dec 4;15(1):98-106. doi: 10.1038/nn.2964.
The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.
细胞质 RIG-I 样螺旋酶 (RLH) 在自身免疫中的作用在中枢神经系统中很大程度上是未知的。使用多发性硬化症的小鼠模型，我们发现缺乏 RLH 衔接蛋白 IPS-1 的小鼠出现了疾病加重的情况，其伴随的炎症明显增加，轴突损伤增加，脱髓鞘增加，致脑炎免疫反应增加。此外，激活 RLH 配体，如 5'-三磷酸 RNA 寡核苷酸，可减少中枢神经系统炎症并改善疾病的临床症状。RLH 刺激抑制了已分化的 T(H)1 和 T(H)17 细胞的维持和扩增，而 T 细胞分化没有改变。值得注意的是，T(H)1 和 T(H)17 的抑制需要树突状细胞上的 I 型干扰素受体的参与，但不需要巨噬细胞或小胶质细胞。这些结果表明 RLH 是中枢神经系统中 T(H)1 和 T(H)17 反应的负调节剂，证明了 RLH 途径对大脑炎症的保护作用，并确立了 RLH 的寡核苷酸配体作为治疗多发性硬化症的潜在治疗方法。
