Innate Immune Cell and Epithelial Subsets Coordinate Airway Responses to Allergen

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RATIONALE: The mechanisms responsible for promoting allergic asthma remain incompletely understood, particularly the role of the crosstalk between innate immune cells and airway epithelium in coordinating the response to inhaled allergen. OBJECTIVE: Identify transcriptional responses to allergen exposure in human airway samples and ex vivo airway epithelial cell (AEC) model systems. METHODS: RNA-sequencing (RNA-seq) analyses were performed on induced sputum samples from individuals with allergic asthma that underwent inhaled allergen challenge. We integrated these results with a single cell RNA-seq (scRNA-seq) data set of epithelial brushings obtained before and after segmental allergen challenge (SAC). Finally, we performed RNA-seq analyses of primary AECs following house dust mite exposure in the context of priming with IL-13 (simulating a type-2 (T2) environment) or IFN-γ (simulating a type-1 (T1) environment). RESULTS: Distinct kinetic patterns were identified in the diverse inflammatory response to allergen in induced sputum samples, including activation of mast cell (MC) and AEC genes. Using the SAC scRNA-seq data set, we demonstrated that MCs modestly increase in the airways following SAC and are a key source of IL5 and IL18 expression. In contrast, basophils are near absent in the airways at baseline but are present in the airways following allergen challenge and are key sources of IL4 and IL13 expression. RNA-seq analyses of AECs in ex vivo culture demonstrate a core AEC allergen response enriched in genes associated with glycolysis and cadherin binding but is significantly altered in the presence of either IL-13 or IFN-γ exposure. Finally, we integrate these data sets to demonstrate that basophil chemotaxis to the airways in allergic asthma is partly mediated by epithelial-derived CCL26. CONCLUSION: Allergen challenge promotes diverse pro-inflammatory transcriptional responses in the airways, and MCs, basophils, and AECs play distinct but critical roles in coordinating this response. However, airway responses to allergen may vary considerably based on the baseline airway inflammatory endotype.

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