Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2022 Apr 19;13:695576. doi: 10.3389/fimmu.2022.695576. eCollection 2022.
Aberrant innate immune responses to the gut microbiota are causally involved in the pathogenesis of inflammatory bowel diseases (IBD). The exact triggers and main signaling pathways activating innate immune cells and how they modulate adaptive immunity in IBD is still not completely understood. Here, we report that the PI3K/PTEN signaling pathway in dendritic cells enhances IL-6 production in a model of DSS-induced colitis. This results in exacerbated Th1 cell responses and increased mortality in DC-specific PTEN knockout (PTEN) animals. Depletion of the gut microbiota using antibiotics as well as blocking IL-6R signaling rescued mortality in PTEN mice, whereas adoptive transfer of Flt3L-derived PTEN DCs into WT recipients exacerbated DSS-induced colitis and increased mortality. Taken together, we show that the PI3K signaling pathway in dendritic cells contributes to disease pathology by promoting IL-6 mediated Th1 responses.
异常的固有免疫反应对肠道微生物群在炎症性肠病（IBD）的发病机制中起因果作用。确切的触发因素和主要信号通路激活固有免疫细胞，以及它们如何在 IBD 中调节适应性免疫仍然不完全清楚。在这里，我们报告树突状细胞中的 PI3K/PTEN 信号通路增强了 DSS 诱导的结肠炎模型中的 IL-6 产生。这导致 Th1 细胞反应加剧，PTEN 敲除（PTEN）动物的死亡率增加。使用抗生素耗尽肠道微生物群以及阻断 IL-6R 信号可挽救 PTEN 小鼠的死亡率，而将 Flt3L 衍生的 PTEN DC 过继转移到 WT 受体中则加剧了 DSS 诱导的结肠炎并增加了死亡率。总之，我们表明树突状细胞中的 PI3K 信号通路通过促进 IL-6 介导的 Th1 反应促进疾病病理学。
