IL-25 improves diabetic wound healing through stimulating M2 macrophage polarization and fibroblast activation

Background: Persistent chronic inflammation is one of the main pathogenic characteristics of diabetic wounds. The resolution of inflammation is important for wound healing and extracellular matrix (ECM) formation. Interleukin (IL)-25 can modulate the function of macrophage and fibroblast, but its role and mechanism of action in the treatment of diabetic wounds remain largely unclear. Methods: The mice were categorized into diabetic, diabetic + IL-25 and control groups. Human monocytic THP-1 cell line and human dermal fibroblast (HDF) were stimulated under different IL-25 conditions. Then, flow cytometry, real-time quantitative PCR (RT-qPCR), Western blot (WB), and immunofluorescence (IF) assays were carried out. Results: The mice in diabetes group (DG) had a slower wound healing rate, more severe inflammation, less blood vessels and more disordered collagen than those in control group (CG). Intradermal injection of IL-25 could improve these conditions. IL-25 promoted M2 macrophage polarization and fibroblast activation in DG and high glucose environment. The phenomenon, which was dependent on PI3K/AKT/mTOR and TGF-beta/SMAD signaling, could be blocked by LY294002 and LY2109761. Conclusion: IL-25 may serve as a therapeutic target to improve wound healing in diabetic mice.