Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
J Exp Med. 2018 Nov 5;215(11):2868-2886. doi: 10.1084/jem.20171029. Epub 2018 Sep 25.
A coding variant of the inflammatory bowel disease (IBD) risk gene has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo IL-22 treatment in and / mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death. Therapeutic blockade of IFN-I signaling ameliorates IL-22-induced ileal inflammation in mice. Our data demonstrate an unexpected role of in coordinating the outcome of IL-22 signaling in the intestinal epithelium.
炎症性肠病（IBD）风险基因的一个编码变异与自噬缺陷和内质网（ER）功能失调有关。IL-22 是一种屏障保护细胞因子，可在肠道黏膜中诱导再生和抗微生物反应。我们表明 ATG16L1 可在肠道上皮细胞中严格协调 IL-22 信号转导。IL-22 刺激在生理上导致短暂的 ER 应激，随后激活 STING 依赖性 I 型干扰素（IFN-I）信号转导，在肠道类器官中增强。IFN-I 信号转导增强了 IL-22 下游上皮细胞 TNF 的产生，并有助于坏死性细胞死亡。在 和 / 小鼠体内给予 IL-22 治疗可增强内源性回肠炎，并导致广泛的坏死性上皮细胞死亡。IFN-I 信号转导的治疗性阻断可改善 小鼠中 IL-22 诱导的回肠炎。我们的数据表明在肠道上皮细胞中， 协调 IL-22 信号转导结果的作用出乎意料。
