Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage

• DOI: 10.1016/j.immuni.2015.06.024
• Publication Date: 2015-08-26T00:41:47Z
• Authors: Xinyang Song; Dai Dai; Xiao He; Shu Zhu; Yikun Yao; Hanchao Gao; Jingjing Wang; Fangfang Qu; Ju Qiu; Honglin Wang; Xiaoxia Li; Nan Shen; Youcun Qian
• Keywords: Immunology; Blotting, Western; Mice, Transgenic; 03 medical and health sciences; Cell Line, Tumor; Immunology and Allergy; Animals; Humans; Intestinal Mucosa; Cells, Cultured; Adaptor Proteins, Signal Transducing; Oligonucleotide Array Sequence Analysis; Mice, Knockout; 0303 health sciences; Gene Expression Profiling; Microbiota; Interleukin-17; Colitis; Intestines; Mice, Inbred C57BL; Infectious Diseases; HEK293 Cells; Fibroblast Growth Factor 2; HT29 Cells; HeLa Cells

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.