STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways.
STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways.
复制标题
DOI：
10.4049/jimmunol.2001317
复制
发表时间：
2021-05-01
期刊：
影响因子：
--
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
Johnson BM;Uchimura T;Gallovic MD;Thamilarasan M;Chou WC;Gibson SA;Deng M;Tam JW;Batty CJ;Williams J;Matsushima GK;Bachelder EM;Ainslie KM;Markovic-Plese S;Ting JP
cGAS-环GMP-AMP（cGAMP）-IFN基因刺激物（STING）途径诱导强大的I型IFN（IFN-I）应答，并且是用于增强癌症免疫疗法和疫苗中的免疫的主要候选物。IFN-I还具有在几种自身免疫性疾病中表现出的免疫调节功能，并且是复发缓解型多发性硬化症的一线治疗。然而，它仅是中等有效的，并且可以在受体中诱导不良反应和中和抗体。在自身免疫中靶向cGAMP是未探索的，并且由于其受体STING的细胞内位置而代表了挑战。我们使用微粒（MP）包封的cGAMP来增加细胞递送，实现剂量节省并降低潜在毒性。在C57 BL/6实验性过敏性脑脊髓炎（EAE）模型中，给予封装在MP中的cGAMP（cGAMP MP）以STING依赖性方式治疗性地保护小鼠免受EAE，而可溶性cGAMP无效。在复发-缓解模型中也观察到保护作用。重要的是，cGAMP MP在疾病高峰时保护EAE，并且比rIFN-β更有效。在机制上，cGAMP MP表现出IFN-I依赖性和非依赖性免疫抑制作用。此外，它诱导免疫抑制细胞因子IL-27，而不需要IFN-I。这通过激活ERK和CREB增加了IL-10的表达。IL-27和随后的IL-10是减轻自身反应性的最重要的细胞因子。重要的是，cGAMP MP促进了复发缓解型多发性硬化患者PBMC中的IFN-I以及免疫调节细胞因子IL-27和IL-10。总的来说，这项研究揭示了cGAMP以前未被重视的免疫调节作用，可以用来抑制T细胞自身反应性。
The cGAS–cyclic GMP–AMP (cGAMP)–stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing–remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)–encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing–remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-β. Mechanistically, cGAMP MPs showed both IFN-I–dependent and –independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing–remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.
登录
查看更多内容
DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
影响因子：
8.8
作者：
Ahn J;Son S;Oliveira SC;Barber GN
通讯作者：
Barber GN
激活的 STING 通过 c-jun/CCL22 信号增强舌鳞状细胞 HPV 相关癌变过程中 Tregs 的浸润
DOI：
10.1016/j.bbadis.2015.08.011
发表时间：
2015-11-01
影响因子：
6.2
作者：
Ding, Liang;Huang, Xiao-Feng;Hou, Ya-Yi
通讯作者：
Hou, Ya-Yi
DOI：
10.1073/pnas.1215006109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Ahn, Jeonghyun;Gutman, Delia;Barber, Glen N.
通讯作者：
Barber, Glen N.
粘膜辅助循环DI-GMP增强了抗原摄取，并选择性地激活了体内的性腺增生效率细胞。
影响因子：
7.7
作者：
Blaauboer SM;Mansouri S;Tucker HR;Wang HL;Gabrielle VD;Jin L
通讯作者：
Jin L