Basophils promote barrier dysfunction and resolution in the atopic skin

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Type 2 cytokines, including interleukin-4 (IL-4) and IL-13, are implicated in both the development and resolution of atopic dermatitis (AD).
• The precise mechanisms by which type 2 cytokines contribute to AD resolution remain largely uncharacterized.

Purpose of the Study:

• To elucidate the cellular players and molecular pathways involved in skin inflammation, barrier impairment, and inflammation resolution within an acute AD model.
• To investigate the specific roles of basophils and key cytokines in the pathogenesis and resolution of AD.

Main Methods:

• An acute mouse model of AD was induced using calcipotriol (MC903).
• Studies involved genetically modified mice (e.g., IL-4/IL-13 overexpression, basophil/eosinophil depletion, IL-4 deficiency, MHC class II deficiency, M-CSF deficient basophils).
• Disease kinetics, keratinocyte differentiation, leukocyte infiltration, and cytokine profiles were assessed using various techniques including transepidermal water loss, histopathology, molecular biology, and spectral flow cytometry.

Main Results:

• Systemically activated basophils were identified as the primary source of IL-4 in the skin during AD.
• Basophils and IL-4 contributed to epidermal hyperplasia and barrier dysfunction by modulating keratinocyte differentiation.
• Basophils, IL-4, and basophil-derived M-CSF suppressed pro-inflammatory cell accumulation while promoting M2-like macrophage expansion and the expression of skin barrier genes.

Conclusions:

• Basophils exhibit a dual function in atopic inflammation, simultaneously contributing to detrimental inflammatory processes and beneficial resolution.
• These findings highlight the complex role of basophils in orchestrating both the progression and resolution of atopic dermatitis.