嗜碱性粒细胞通过LTC4-NMU介导特应性皮炎瘙痒的神经免疫机制

特应性皮炎（atopic dermatitis, AD）是过敏性瘙痒性皮肤病，其瘙痒机制涉及免疫和神经两个系统。已知过敏原暴露和AD瘙痒症状加重密切相关。“过敏原-IgE-肥大细胞-组胺”是经典致痒通路，但其在AD过敏原相关性瘙痒中的作用缺乏论证。我们前期在AD小鼠模型中发现敲除肥大细胞或阻断组胺通路，均无法减轻过敏原诱发性瘙痒，而“嗜碱性粒细胞-白三烯LTC4”通路则起到关键作用。研究表明，感觉神经元活化后释放神经肽调节免疫系统功能。我组预实验结果显示神经调节肽NMU对AD皮肤炎症有调节作用，嗜碱性粒细胞表面表达其受体。本课题从神经免疫角度出发，拟利用转基因动物、单细胞测序、双光子成像、免疫荧光、钙成像等研究方法，结合人体组织和动物模型明确“嗜碱性粒细胞-白三烯LTC4”作用感觉神经元的特征，并探讨瘙痒神经元和NMU在疾病中对嗜碱性粒细胞的调控作用。研究结果将为疾病防控奠定转化医学基础。

Atopic dermatitis (AD) is an allergic and itchy skin disorder. Its itch mechanisms involve the interaction between immunology and neurology. It has been demonstrated that the aggravation of itch symptom is highly related to allergen exposure. Although “allergen-IgE-mast cell-histamine” axis has been recognized as a classical itch pathway, its specific role in allergen-induced itch in AD remains unproven. Our preliminary study showed that in an actively sensitized murine model in the context of AD, mast cell depletion or histamine inhibition was not sufficient to reduce allergen-provoked itch. Strikingly, “basophil-leukotriene C4” was found to be a potential pathway mediating allergen-provoked itch. Accumulating evidence has shown that the activation of sensory neurons induces neuropeptide releasing, which subsequently reforms immune system. Our preliminary data has shown a regulation role played by neuromedin U (NMU) in skin inflammation in the setting of AD. Additionally, the receptor of NMU is expressed by basophils on RNA levels. Based on these previous findings, in this project, we will study human subjects as well as murine models by employing a variety of techniques such as transgenic animals, single-cell RNA sequence, intravital two-photon imaging, immunofluorescence and calcium imaging. Our ultimate goal is to identify the heterogeneity of itch sensory neurons activated by “basophils-LTC4” axis and explore the precise role played by sensory neurons and NMU in basophil regulation. The future findings will build a consolidated foundation for translational research on disease prevention and treatment.