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. Author manuscript; available in PMC: 2022 Apr 26.
Published in final edited form as: Annu Rev Immunol. 2021 Feb 12;39:537–556. doi: 10.1146/annurev-immunol-101819-092536

Figure 4: Pleotropic IL-17 regulates fibrosis, cancer development and wound healing:

Figure 4:

(A) IL-17 promotes fibrosis by acting on fibroblasts, epithelial cells and pro-fibrotic macrophages. IL-17 signals on epithelial cells to secrete profibrotic TGF-β. TGF-β along with IL-17 act on fibroblasts to promote IL-6 production which has pro-fibrotic functions. Other than IL-6, Fibroblasts in presence of IL-17 signaling also secrete chemokines such as IL-8 and CXCL1. CXCL1 then recruits neutrophils, which synthesizes matrix metalloproteinases (MMP) critical for fibrosis development. Besides fibroblasts in presence of IL-17 also produce α-SMA, collagen and ECM proteins necessary for fibrosis. Similarly, IL-17 acting on macrophages produce IL-36g which is important for the generation of fibrosis. (B) Besides, directly promoting tumor formation, IL-17 mainly acts on cancers associated fibroblasts (CAFs) to manifest its pro-tumor functions. IL-17 signaling in CAFs generates VEGF, IL-6 and chemokines all of which has critical protumor roles. VEGF is important for angiogenesis, one of the hallmarks of cancer. IL-6 can directly act of tumor infiltrating lymphocytes to produce more IL-17. CXCL1 on the other hand recruits’ neutrophils to synthesize MMP9 important for angiogenesis. Moreover, IL-17 can block anti-tumor CD8 T cells, critical for fighting cancers, either directly or though CXCL5 driven myeloid derived suppressor cells (MDSCs.) (C) IL-17 function is indispensable for wound healing. IL-17 derived from either conventional CD4+ T cells, γδ+ T cells or CD8+ T cells (Tc17) plays critical role in repairing wounds. IL-17 acting on fibroblasts generate VEGF, CXCL1, REG3α all critical for wound healing. VEGF plays an important role in vascular repair following wound formation. CXCL1 again is important for the recruitment of neutrophils secreting MMP-9, critical for wound repair. Lgr5+ stem cells are also important for wound repair. Synergistic signaling of IL-17R and EGFR on these stem cells are critical for wound repair following injury. Beside IL-17 secretion, Tc17 cells also produce amphiregulin, an important protein for wound repair. Moreover, several studies reported that IL-17 secreted from γδ+ T cells is critical for repairing tight junction proteins such as ZO-1 following DSS mediated gut injuries. Figure adapted from image created with Biorender.com.