Yamanishi Yoshinori, Mogi Kotone, Takahashi Kazufusa, Miyake Kensuke, Yoshikawa Soichiro, Karasuyama Hajime
Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Department of Cellular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Allergy. 2020 Oct;75(10):2613-2622. doi: 10.1111/all.14362. Epub 2020 May 26.
Patients with atopic dermatitis (AD) often show the infiltration of basophils in the affected skin. Because basophils represent only a minor fraction among cellular infiltrates in the skin lesion, the functional significance of skin-infiltrating basophils in AD pathogenesis remains ill-defined. In this study, we aimed to clarify the role of basophils and their effector molecules triggering skin inflammation in oxazolone (OX)-induced murine model of AD.
A panel of mouse strains were sensitized and repeatedly challenged with topical applications of OX to induce AD-like skin inflammation. Both local and systemic Th2 immune responses were analyzed.
Basophils progressively accumulated in the skin lesion but barely in draining lymph nodes (LNs). When basophils were depleted during the elicitation phase, skin inflammation was ameliorated while Th2 cell differentiation in draining LNs remained intact. The expression of IL-4 was highly upregulated in the affected skin, and basophils turned out to be the major producers of IL-4 among cellular infiltrates, suggesting the involvement of basophil-derived IL-4 in the Th2 skin inflammation. Indeed, basophil-specific IL-4-deficient mice displayed attenuated skin inflammation with a marked reduction of IL-4 in the skin lesion, even though cutaneous basophil infiltration and serum levels of IgE remained intact.
Skin-infiltrating basophils promoted OX-induced AD-like skin inflammation through their local production of IL-4, rather than the induction of Th2 cell differentiation in draining LNs. This study suggests that the selective targeting of basophils could be a beneficial strategy in the treatment of a certain type of AD.
特应性皮炎（AD）患者的受累皮肤中常出现嗜碱性粒细胞浸润。由于嗜碱性粒细胞在皮肤病变中的细胞浸润中仅占一小部分，因此皮肤浸润嗜碱性粒细胞在AD发病机制中的功能意义仍不明确。在本研究中，我们旨在阐明嗜碱性粒细胞及其效应分子在恶唑酮（OX）诱导的AD小鼠模型中引发皮肤炎症的作用。
使用一组小鼠品系，通过局部应用OX进行致敏并反复激发，以诱导类似AD的皮肤炎症。分析局部和全身的Th2免疫反应。
嗜碱性粒细胞在皮肤病变中逐渐积累，但在引流淋巴结（LN）中几乎没有。在激发阶段去除嗜碱性粒细胞后，皮肤炎症得到改善，而引流LN中的Th2细胞分化保持完整。IL-4在受累皮肤中的表达高度上调，并且嗜碱性粒细胞是细胞浸润中IL-4的主要产生者，这表明嗜碱性粒细胞衍生的IL-4参与了Th2介导的皮肤炎症。实际上，嗜碱性粒细胞特异性IL-4缺陷小鼠的皮肤炎症减轻，皮肤病变中的IL-4显著减少，尽管皮肤嗜碱性粒细胞浸润和血清IgE水平保持不变。
皮肤浸润的嗜碱性粒细胞通过其在局部产生IL-4促进OX诱导的类似AD的皮肤炎症，而不是通过诱导引流LN中的Th2细胞分化。本研究表明，选择性靶向嗜碱性粒细胞可能是治疗某种类型AD的有益策略。
