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

Abstract

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.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…95 The dysregulated microbiota induces TGFβ1 expression in the model, which in turn triggers FGF2 expression in regulatory T cells. 95 Thus, during acute colitis Th17-derived IL-17 coordinates with Treg-derived FGF2 to repair intestinal epithelial damage. Both T-cell-derived FGF2 and IL-17 protected Rag1-deficient mice from a naive CD4 + T-cell transfer-induced colitis model.…”

“…During colitis, the growth factor FGF2 has been shown to synergize with IL-17 to induce the expression of genes involved in tissue repair and restore the damaged epithelium. 95 Deficiency in either FGF2 or IL-17 leads to impaired epithelial proliferation, uncontrolled Enterobacteriaceae outgrowth, and consequently worsened DSS-induced colitis pathology. 95 The dysregulated microbiota induces TGFβ1 expression in the model, which in turn triggers FGF2 expression in regulatory T cells.…”

“…95 Deficiency in either FGF2 or IL-17 leads to impaired epithelial proliferation, uncontrolled Enterobacteriaceae outgrowth, and consequently worsened DSS-induced colitis pathology. 95 The dysregulated microbiota induces TGFβ1 expression in the model, which in turn triggers FGF2 expression in regulatory T cells. 95 Thus, during acute colitis Th17-derived IL-17 coordinates with Treg-derived FGF2 to repair intestinal epithelial damage.…”

“…Both T-cell-derived FGF2 and IL-17 protected Rag1-deficient mice from a naive CD4 + T-cell transfer-induced colitis model. 95 However, IL-17F exacerbated the DSS-induced intestinal inflammation because Il17f-deficient mice were resistant to DSS challenge. 45 Psoriasis, which is a relapsing skin inflammatory disorder, is characterized by hyperplasia of the dermis.…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…Anti‐IL‐17 and anti‐IL‐17RA antibodies are effective to treat patients with psoriasis and psoriatic arthritis 11, 12, 13. Interleukin‐17 is also important for the maintenance of intestinal barrier integrity and its functional deficiency causes the development of inflammatory bowel diseases 14, 15, 16. In contrast, suppression of IL‐17F, another highly homologous member of IL‐17 family, is suggested to be beneficial for the treatment of inflammatory bowel diseases 17…”