Sensitizer-Induced Basophils Accelerate Skin Re-Epithelialization via IL-4/IL-13-Mediated Macrophage Polarization

Background: Atopic dermatitis (AD) patients exhibit a paradox of impaired skin barrier with intense itching, yet often demonstrate rapid re-epithelialization after scratching. While basophils are key effector cells in allergic inflammation, their role in the subsequent tissue repair remains unexplored. Objective: We investigated whether basophils, recruited during sensitized skin responses, contribute to wound healing. Methods: Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we mapped basophil infiltration and activation in sensitizer (oxazolone)-induced skin injury models. We employed genetic (Mcpt8^CT/+R26^DTA/+) and antibody-mediated (anti-FcεRI) basophil depletion, as well as basophil-specific Il4/Il13 knockout mice (Il4/13^fl/flMcpt8^CT/+) to define their functional contribution. Macrophage polarization was assessed by flow cytometry, RT-qPCR, and immunohistochemistry. Results: We identified a significant enrichment of basophils in wounded skin, peaking at day 3–6 post-injury. Sensitizer-challenge enhanced basophil recruitment and accelerated wound closure, angiogenesis, and re-epithelialization. Depletion of basophils severely impaired these repair processes. Mechanistically, basophils were the predominant source of IL-4 and IL-13 in the early wound microenvironment. These cytokines were essential for driving macrophage polarization toward a pro-repair M2 phenotype. Loss of IL4/IL13 specifically in basophils phenocopied the healing defects observed in basophil-deficient mice, and this could be rescued by local cytokine administration. Conclusion: Our study uncovers a novel pro-repair function of basophils in sensitizer-exposed skin. Beyond their well-known role in provoking itch and inflammation, basophils are critical for initiating type 2 immune-mediated tissue regeneration via IL-4/IL-13-dependent macrophage reprogramming. This axis represents a promising therapeutic target for chronic wounds, particularly in the context of allergic skin disorders.