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

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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.