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，导致患者健康的实质性损害。哮喘的发病率在过去几十年中显著增加，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。尽管传统的哮喘研究主要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起着重要作用。已经提出上皮细胞通过感知环境空气变应原并释放驱动变应性炎症表型的免疫调节因子在疾病的致敏过程中起决定性作用。然而，在肺基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应答导致哮喘发病机制仍然是难以捉摸的。在这个项目提案中，我们的目的是研究炎症和细胞死亡途径在肺上皮细胞和间充质细胞中的作用，在2型免疫的调节和过敏性气道炎症的发病机制。在遗传小鼠模型中使用上皮和间充质细胞特异性靶向MyD 88，我们将解决TLR和IL-1 R1信号传导在疾病发病机制中的细胞特异性机制。此外，我们将通过实验阐明肺上皮细胞的免疫原性死亡可能与气道过敏性炎症的发病机制有关的假设。具体而言，我们将使用相关的遗传小鼠模型，探讨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性凋亡在哮喘发病机制中的作用。总之，这些研究将解决基质细胞特异性作用的炎症和细胞死亡信号通路在小鼠模型气道过敏性炎症的发病机制，并将相关的更好地理解的机制，调节人类哮喘的发病机制。

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.