Basophils in Skin-Mediated Sensitization Drive Subsequent Lung Inflammation in Airway-Challenged Mice.

Abstract

BACKGROUND Atopic dermatitis (AD) and asthma are observed as epidemiologically linked allergic comorbidities, both characterized by elevated systemic IgE levels and type 2 immunity. Basophils play a pivotal role in these responses by producing interleukin-4 (IL-4), which is essential for IgE synthesis and allergic inflammation. However, their specific impact on the progression from AD to asthma remains unclear. METHODS We utilized an AD model in basophil-deficient Mcpt8Cre mice and temporarily basophil-depleted mice, where topical application of the vitamin D analog MC903 induced the alarmin TSLP, resulting in AD-like symptoms. In addition, we topically applied ovalbumin (OVA) as a model allergen to trace the allergen-specific immune response. We determined allergen-specific antibody formation by analysis of the germinal center reaction and measured serum antibody concentrations and IgE loading of basophils in the spleen and lung. We further challenged mice sensitized via the skin in anaphylaxis and allergic lung inflammation models. RESULTS Our results demonstrate that basophils promote loss of skin barrier integrity, allergen-specific IgE formation, and subsequent allergic responses. Basophil depletion selectively during sensitization significantly reduced IgE-dependent anaphylaxis and lung inflammation. In challenged lungs, reduced inflammation and eosinophilia were accompanied by lower levels of chemokines CCL17 and CCL24, which attract Th2 cells and eosinophils, respectively. Notably, Il4 and Il13 were not affected by basophil depletion during sensitization but were reduced in mice that permanently lack basophils. CONCLUSION We find that basophils promote IgE formation and lung sensitization to skin-encountered allergens and drive secondary allergen-induced lung inflammation. We separate the role of basophils in sensitization from their effector function during anaphylaxis or lung inflammation relevant to envision novel strategies to prevent the development of allergic comorbidities.