Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Cell Rep. 2021 May 11;35(6):109113. doi: 10.1016/j.celrep.2021.109113.
STING modulates immunity by responding to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with STING gain-of-function mutations develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by inflammatory or fibrosing lung disease. We hypothesized that hyperresponsiveness of gain-of-function STING to bacterial CDNs might explain autoinflammatory lung disease in SAVI mice. We report that depletion of gut microbes with oral antibiotics (vancomycin, neomycin, and ampicillin [VNA]) nearly eliminates lung disease in SAVI mice, implying that gut microbes might promote STING-associated autoinflammation. However, we show that germ-free SAVI mice still develop severe autoinflammatory disease and that transferring gut microbiota from antibiotics-treated mice to germ-free animals eliminates lung inflammation. Depletion of anaerobes with metronidazole abolishes the protective effect of the VNA antibiotics cocktail, and recolonization with the metronidazole-sensitive anaerobe Bacteroides thetaiotaomicron prevents disease, confirming a protective role of a metronidazole-sensitive microbe in a model of SAVI.
STING 通过对细菌和内源性环二核苷酸（CDNs）的反应来调节免疫。具有 STING 功能获得性突变的人类和小鼠会发展出一种称为 STING 相关血管病（SAVI）的综合征，其特征是炎症性或纤维化性肺病。我们假设功能获得性 STING 对细菌 CDN 的高反应性可能解释了 SAVI 小鼠的自身炎症性肺病。我们报告称，用口服抗生素（万古霉素、新霉素和氨苄青霉素[VNA]）耗尽肠道微生物几乎可以消除 SAVI 小鼠的肺部疾病，这意味着肠道微生物可能会促进 STING 相关的自身炎症。然而，我们表明无菌 SAVI 小鼠仍然会发生严重的自身炎症性疾病，并且将抗生素处理过的小鼠的肠道微生物群转移到无菌动物中可以消除肺部炎症。用甲硝唑耗尽厌氧菌会消除 VNA 抗生素鸡尾酒的保护作用，并且用甲硝唑敏感的厌氧菌 Bacteroides thetaiotaomicron 重新定植可以预防疾病，这证实了一种在 SAVI 模型中对甲硝唑敏感的微生物的保护作用。
