The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China.
Immunity. 2015 Sep 15;43(3):488-501. doi: 10.1016/j.immuni.2015.06.024. Epub 2015 Aug 25.
The intestinal epithelial barrier plays a critical role in the mucosal immunity. However, it remains largely unknown how the epithelial barrier is maintained after damage. Here we show that growth factor FGF2 synergized with interleukin-17 (IL-17) to induce genes for repairing of damaged epithelium. FGF2 or IL-17 deficiency resulted in impaired epithelial proliferation, increased pro-inflammatory microbiota outgrowth, and consequently worse pathology in a DSS-induced colitis model. The dysregulated microbiota in the model induced transforming growth factor beta 1 (TGFβ1) expression, which in turn induced FGF2 expression mainly in regulatory T cells. Act1, an essential adaptor in IL-17 signaling, suppressed FGF2-induced ERK activation through binding to adaptor molecule GRB2 to interfere with its association with guanine nucleotide exchange factor SOS1. Act1 preferentially bound to IL-17 receptor complex, releasing its suppressive effect on FGF2 signaling. Thus, microbiota-driven FGF2 and IL-17 cooperate to repair the damaged intestinal epithelium through Act1-mediated direct signaling cross-talk.
肠道上皮屏障在黏膜免疫中起着关键作用。然而，上皮屏障在损伤后如何被维持，目前还在很大程度上不清楚。在这里，我们发现生长因子 FGF2 与白细胞介素-17（IL-17）协同作用，诱导修复受损上皮的基因表达。FGF2 或 IL-17 的缺乏导致上皮细胞增殖受损，促炎微生物群过度生长，从而在 DSS 诱导的结肠炎模型中导致更严重的病理。模型中失调的微生物群诱导转化生长因子β 1（TGFβ1）表达，反过来又诱导 FGF2 主要在调节性 T 细胞中表达。Act1 是 IL-17 信号通路中的一个重要衔接蛋白，通过与衔接分子 GRB2 结合，干扰其与鸟苷酸交换因子 SOS1 的结合，从而抑制 FGF2 诱导的 ERK 激活。Act1 优先结合 IL-17 受体复合物，从而解除其对 FGF2 信号通路的抑制作用。因此，微生物群驱动的 FGF2 和 IL-17 通过 Act1 介导的直接信号交叉对话，共同修复受损的肠道上皮细胞。
