Genetic and Epigenetic Programming of Allergic Airway Inflammation

It is appreciated that the high prevalence of asthma over the last decades reflects the interaction of susceptibility genes in affected individuals with environmental and social changes ushered by modernity [1]. A key feature of asthma is chronic airway inflammation driven and/or exacerbated by ongoing exposure to allergens and pollutants, most notably ambient particulate matter (PMs). The persistence of such inflammation suggests the derailment of normative countervailing immune regulatory mechanisms that would otherwise limit its scope. In that regard, we have identified Notch4 expression in lung regulatory T (TR) cells as a key mechanism that disrupts lung tissue homeostatic immune regulation to promote allergic airway inflammation. Notch4 is upregulated by IL-6 signaling in TR cells to activate downstream intermediates including the Wnt and Hippo pathways to promote airway Th2 and Th17 immune responses, respectively. Notch4 expression is augmented by PM, which act to induce the expression of the Notch receptor ligand Jag1 in alveolar macrophages as well as the production of IL-6. Finally, Notch4 is also upregulated on lung TR cells in the context of viral infections, thus providing a potential link between viral infections and exacerbation of allergic airway inflammation. Accordingly, our central hypothesis is that Notch4 signaling in TR cells integrates cues by allergens, pollutants and viruses to license tissue allergic inflammation. To address this hypothesis, we propose under Aim 1 to investigate the mechanisms by which Notch4 subverts TR cell function to promote allergic airway inflammation. We will investigate the role of the Notch4-activated Hippo pathway in TR cell destabilization, leading to the generation of tissue resident ex-TR cells that promote airway inflammation. We will also investigate the role of the Wnt pathway downstream of Notch4 in driving Th2 pathology, as well as the interaction of Notch4 with environmental inputs such as PMs of different sources and physiochemical properties to promote airway inflammation. We further propose under Aim 2 to investigate the role of Growth and Differentiation Factor 15 (GDF15) as a cytokine produced by lung TR cells in a Notch4-Wnt pathway-dependent manner that may contribute to tissue inflammation and pathology by acting via its receptor GFRAL on ILC2 to drive their activation and expansion. The relationship between TR cell Notch4, GDF15, IL-6 and BMI will be explored in a cohort of asthmatic subjects. Finally, under Aim 3 we will examine the role of TR cell-intrinsic viral sensing pathways alone and in synergy with Notch4 in promoting virus and allergen-induced inflammation. Our studies will help elucidate novel mechanisms fundamental to the biology of allergic airway inflammation and its augmentation by pollutants, obesity and viral infections.