Abstract
Chronic non-healing wounds are among the most common complications of diabetes, highlighting the urgent need for effective and accessible therapeutic strategies. Although microwave therapy has shown promise in promoting tissue repair, its underlying mechanisms in diabetic wound healing remain unclear. This study investigated the therapeutic effects of microwave therapy on diabetic wound healing and its potential modulation of the Interleukin-33 (IL-33) /ST2 signaling pathway. Full-thickness excisional wounds were established in C57BL/6 mice, categorized into normal control / wild-type (CON/WT), diabetic (DM), and ST2-deficient (ST2-/-) groups. Mice received optimized microwave treatment (10 watts (W) for 10 min (min) daily), with or without IL-33-enriched macrophage supernatant (IL-33-MS). Wound healing outcomes were evaluated by histology, immunofluorescence, and gene expression analyses. In vitro experiments using RAW264.7 macrophages and HaCaT keratinocytes assessed IL-33 induction, macrophage polarization, and keratinocyte migration. Microwave treatment significantly accelerated wound healing in diabetic mice by enhancing granulation tissue formation, collagen remodeling, neovascularization, and myofibroblast activation. This effect was accompanied by increased IL-33 expression, particularly in macrophages, along with upregulation of M2 markers (CD206, IL-4, YM1) and downregulation of M1 markers (iNOS, Tnf-α). In ST2-/- mice, microwave therapy failed to promote wound repair, indicating that the IL-33/ST2 axis is essential for its pro-healing effect. IL-33-MS promoted wound closure in WT but not in ST2-/- mice. In vitro, microwave exposure upregulated IL-33 in macrophages and enhanced M2 polarization and HaCaT cell migration via ST2-dependent signaling. Microwave therapy facilitates diabetic wound healing by activating the IL-33/ST2 pathway, promoting M2 macrophage polarization, and improving the wound microenvironment. These findings provide mechanistic insight into the immunomodulatory effects of microwave therapy and support its potential as a non-invasive strategy for chronic diabetic wound management.