IFN-γ⁺ IL-17⁺ Th17 cells regulate fibrosis through secreting IL-21 in systemic scleroderma

This study aimed to explore the function of IFN-γ⁺ IL-17⁺ Th17 cells on fibrosis in systemic scleroderma (SSc). Blood and skin samples were collected from 20 SSc cases and 10 healthy individuals. The percentage of IFN-γ⁺ IL-17⁺ Th17 cells was detected using flow cytometry. The in vitro induction of IFN-γ⁺ IL-17⁺ Th17 cells was performed adopting PHA and rIL-12. Gene expression was detected via quantitative real-time polymerase chain reaction (qRT-PCR), whereas western blot analysis was adopted for protein analysis. The distribution of IFN-γ⁺ IL-17⁺ Th17 cells was significantly increased in SSc cases and positively correlated with SSc stages (P = .031), disease duration (P = .016), activity (P = .025) and skin scores (P < .001). In vitro, IFN-γ⁺ IL-17⁺ Th17 cells could promote the expressions of α-SMA and COL1A1, revealing increased fibroblasts' proliferation and enhanced collagen-secreting capacity. In addition, IL-21 expression was significantly increased in co-culture medium of IFN-γ⁺ IL-17⁺ Th17 cells and fibroblasts (P < .001). IL-21 neutralizer treatment resulted in the down-regulation of α-SMA and COL1A1. IL-21 was confirmed as an effector of IFN-γ⁺ IL-17⁺ Th17 cells in fibrosis process. The distribution of IFN-γ⁺ IL-17⁺ Th17 cells was significantly increased in SSc cases and positively correlated with disease activity. IFN-γ⁺ IL-17⁺ Th17 cells could promote fibroblast proliferation and enhance collagen-secreting ability via producing IL-21, thus contributing to fibrosis in SSc.