Inhibition of Th2 Differentiation Accelerates Chronic Wound Healing by Facilitating Lymphangiogenesis

Background/Objectives: Chronic wounds pose a significant healthcare burden, and there remains no effective animal model for study. We aimed to develop a mouse model of chronic wounds that remain open for at least 4 weeks and to investigate the role of the lymphatic system in wound healing. Methods: Full-thickness excisional wounds were created on the dorsal surface of mouse tails to simulate chronic wounds. Lymphatic drainage was assessed using FITC-dextran lymphangiography. Histology and immunofluorescence were used to analyze immune cell infiltration. The effect of inhibiting Th2 differentiation via IL-4 and IL-13 neutralization on wound closure was also evaluated. Results: Our chronic wound model was successful, and wounds remained open for 4 weeks. Impaired lymphatic drainage was observed extending beyond the wound area. Increased CD4+ T-helper cell infiltration and Th2 cell accumulation were observed in the impaired lymphatic drainage zone. Inhibition of IL-4 and IL-13 accelerated wound healing. Conclusions: Impaired lymphatic drainage and Th2-mediated inflammation contribute to delayed healing, and gradients of lymphatic fluid flow are associated with spatial differences in lymphangiogenesis. Targeting Th2 cytokines may offer a novel therapeutic approach for chronic wounds.