Journal
IMMUNITY
Volume 43, Issue 3, Pages 488-501Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.06.024
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Funding
- National Natural Science Foundation of China [81430036, 81230075, 91429307, 31329002, 91329301, 31300710, 81421001]
- 973 Program [2013CB944904, 2014CB541902]
- Science and Technology Commission of Shanghai Municipality [13JC1408900]
- Collaborative Innovation Center of Systems Biomedicine
- Chinese Academy of Sciences [KJZD-EW-L01-3]
- State Key Laboratory of Oncogenes and Related Genes [91-14-05]
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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 (TGF beta 1) 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.
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