Extracellular vesicles package dsDNA to aggravate Crohn's disease by activating the STING pathway.
Extracellular vesicles package dsDNA to aggravate Crohn's disease by activating the STING pathway.
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DOI：
10.1038/s41419-021-04101-z
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发表时间：
2021-08-27
影响因子：
9
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Zhao F;Zheng T;Gong W;Wu J;Xie H;Li W;Zhang R;Liu P;Liu J;Wu X;Zhao Y;Ren J
克罗恩病（CD）是一种肠道免疫功能失调疾病。细胞外囊泡（EVs）是膜封闭的颗粒，充满功能分子，如核酸。近年来，研究表明ev通过实现肠细胞间的细胞间通讯参与了CD的发展。然而，携带从肠道炎症部位脱落的双链DNA （dsDNA）的ev在CD中的作用尚未得到研究。我们从小鼠结肠炎和乳糜泻患者的血浆或结肠灌洗液中分离出ev。外泌体dsDNA（包括mtDNA和nDNA）水平在小鼠结肠炎和活动性人CD中显著升高，且与疾病活动性呈正相关。此外，STING通路的激活在CD中得到了验证。来自活跃的人CD血浆的ev在体外触发巨噬细胞的STING激活。来自lps损伤的结肠上皮细胞的ev也通过激活STING途径增加巨噬细胞的炎症，但在去除外泌体dsDNA后，这种作用消失。这些发现在sting缺陷小鼠和巨噬细胞中得到进一步证实。STING缺乏可显著改善结肠炎。此外，我们还评估了EVs释放抑制剂GW4869的潜在治疗效果。GW4869的应用通过抑制STING激活成功改善了小鼠结肠炎。综上所述，外泌体dsDNA通过激活巨噬细胞的STING途径促进肠道炎症，并作为CD的潜在机制生物标志物和治疗靶点。
Crohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.
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