Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS
Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS
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DOI：
10.1038/nn.2964
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发表时间：
2012-01-01
影响因子：
25
通讯作者：
Prinz, Marco
中科院分区：
文献类型：
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作者：
Dann, Angela;Poeck, Hendrik;Prinz, Marco
在自身免疫过程中，细胞溶质RIG-I样解旋酶（RLH）在CNS中的作用在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适配器IPS-1的小鼠发展为加重的疾病，伴随着明显更高的炎症，增加的轴突损伤和升高的脱髓鞘以及增加的致脑炎免疫应答。此外，RLH配体如5 '-三磷酸RNA寡核苷酸的活化减少了CNS炎症并改善了疾病的临床体征。RLH刺激抑制了定型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抑制需要树突状细胞上的I型干扰素受体参与，而不是巨噬细胞或小胶质细胞。这些结果鉴定了RLH作为CNS中T（H）1和T（H）17应答的负调节剂，证明了RLH途径对脑炎症的保护作用，并建立了RLH的寡核苷酸配体作为治疗多发性硬化症的潜在治疗剂。
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.