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

Abstract

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. We investigated whether basophils, recruited during sensitized skin responses, contribute to wound healing. 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. 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. 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.