Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis.
Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis.
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皮肌炎中血浆衍生的含DNA的细胞外囊泡诱导STING介导的促炎反应
DOI：
10.7150/thno.59152
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Werth VP
中科院分区：
文献类型：
--
作者：
Li Y;Bax C;Patel J;Vazquez T;Ravishankar A;Bashir MM;Grinnell M;Diaz D;Werth VP
目的：细胞外囊泡（EV）是存在于各种体液中的脂质双层膜囊泡，并且已经涉及自身免疫性疾病的发病机制。I型干扰素（IFN），特别是IFN-β，在皮肌炎（DM）中独特地升高。干扰素基因刺激物（STING）在I型IFN信号传导中充当关键的核酸传感器和衔接子，可能对糖尿病等自身免疫性疾病产生影响。在目前的研究中，我们研究了循环EV是否有助于DM的促炎作用，这些促炎反应是否由STING信号通路介导，如果是，STING被激活的机制是什么。研究方法：我们从健康对照（HC）和DM患者的血浆中收集并表征EV;通过ELISA分析它们触发促炎细胞因子释放的能力，并使用免疫印迹和免疫荧光染色探索STING信号通路激活。STING信号通路抑制剂和RNAi用于进一步研究STING是否参与EV触发的促炎反应。利用DNase/脂质去稳定剂消化EV及其捕获的DNA内容物，以评估EV如何触发DM中STING介导的促炎反应。结果：从DM血浆中分离的EV触发促炎细胞因子，包括I型IFN释放和STING信号通路激活。活化的STING途径优先由EV捕获的dsDNA介导。STING或其下游信号蛋白的抑制减弱了EV介导的促炎反应。结论：血浆来源的、含有DNA的EV在DM中诱导STING介导的促炎症作用。靶向STING通路可能是糖尿病的潜在治疗方法。
Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.
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DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.3
作者：
Huard, C.;Gulla, S. V.;Greenberg, S. A.
通讯作者：
Greenberg, S. A.
影响因子：
15.9
作者：
Guertler, Claudia;Bowie, Andrew G.
通讯作者：
Bowie, Andrew G.
影响因子：
10.6
作者：
Devhare PB;Ray RB
通讯作者：
Ray RB
外泌体 PD-L1 有助于免疫抑制并与抗 PD-1 反应相关
影响因子：
64.8
作者：
Chen G;Huang AC;Zhang W;Zhang G;Wu M;Xu W;Yu Z;Yang J;Wang B;Sun H;Xia H;Man Q;Zhong W;Antelo LF;Wu B;Xiong X;Liu X;Guan L;Li T;Liu S;Yang R;Lu Y;Dong L;McGettigan S;Somasundaram R;Radhakrishnan R;Mills G;Lu Y;Kim J;Chen YH;Dong H;Zhao Y;Karakousis GC;Mitchell TC;Schuchter LM;Herlyn M;Wherry EJ;Xu X;Guo W
通讯作者：
Guo W