Role of inflammatory and cell death pathways in epithelial and mesenchymal cells of the lung in the regulation of type 2 immunity and the pathogenesis of allergic airway inflammation

哮喘是一种慢性气道炎症性疾病，会严重损害患者的健康。在过去几十年中，哮喘的发病率显著增加，特别是在发达国家，造成了重大的健康和社会经济负担。尽管进行了广泛的研究，但对哮喘的病因和发病机制仍知之甚少。虽然传统的哮喘研究集中在免疫细胞的功能上，但最近的研究表明肺间质细胞在疾病发病机制中的重要贡献。上皮细胞通过感知环境空气过敏原和释放驱动过敏性炎症表型的免疫调节因子，在疾病的致敏过程中发挥决定性作用。然而，在肺间质细胞中起作用的细胞和分子机制和途径，以及对过敏原的不适应免疫反应导致哮喘的发病机制仍然难以捉摸。本课题拟探讨肺上皮细胞和间充质细胞炎症和细胞死亡通路在2型免疫调控中的作用及变应性气道炎症的发病机制。利用基因小鼠模型中上皮细胞和间充质细胞特异性靶向MyD88，我们将探讨TLR和IL-1R1信号在疾病发病机制中的细胞特异性机制。此外，我们将通过实验解决肺上皮细胞免疫原性死亡可能与气道变应性炎症发病机制有关的假设。具体来说，我们将使用相关的遗传小鼠模型来研究FADD/caspase-8介导的肺上皮细胞凋亡和RIP激酶介导的肺上皮细胞坏死在哮喘发病机制中的作用。总之，这些研究将解决小鼠模型中炎症和细胞死亡信号通路在气道变应性炎症发病机制中的基质细胞特异性作用，并将与更好地理解调节人类哮喘发病机制相关。

Asthma is a chronic inflammatory disorder of the airways that leads to a substantial compromise of patients' health. The incidence of asthma has markedly increased in the past few decades, particularly in developed countries, posing a major health and socioeconomic burden. Despite extensive research efforts, the etiology and the mechanisms responsible for the pathogenesis of asthma remain poorly understood. Although traditionally asthma research focused on the function of immune cells, recent studies have indicated an important contribution of lung stromal cells in disease pathogenesis. Epithelial cells have been proposed to play a decisive role in the sensitization process of the disease by sensing environmental aeroallergens and releasing immunomodulatory factors driving the allergic inflammatory phenotype. However the cellular and molecular mechanisms and pathways that operate in lung stromal cells and are responsible for the maladapted immune response to allergens resulting in the pathogenesis of asthma remain elusive. In this project proposal, we aim to investigate the role of inflammatory and cell death pathways in epithelial and mesenchymal cells of the lung in the regulation of type 2 immunity and the pathogenesis of allergic airway inflammation. Using epithelial and mesenchymal cell - specific targeting of MyD88 in genetic mouse models we will address the cell-specific mechanisms of TLR and IL-1R1 signalling in disease pathogenesis. In addition, we will experimentally address the hypothesis that immunogenic death of lung epithelial cells may be implicated in the pathogenesis of airway allergic inflammation. Specifically, we will address the role of FADD/caspase-8-mediated apoptosis and RIP kinase-mediated necroptosis of lung epithelial cells in the pathogenesis of asthma using relevant genetic mouse models. Together, these studies will address the stromal cell specific role of inflammatory and cell death signalling pathways in the pathogenesis of airway allergic inflammation in mouse models and will be relevant for the better understanding of the mechanisms regulating the pathogenesis of asthma in humans.