Epithelial dectin-1 inhibits IL-33 by preventing aberrant HIF-1a activation 2376

Abstract Description Dysregulated type 2 immune responses mediate airway allergic diseases such as asthma and chronic rhinosinusitis. We previously showed that epithelial dectin-1 interaction with invertebrate tropomyosin, a ubiquitous component of house dust mite (HDM), protects against aberrant type 2 responses by inhibiting interleukin-33 (IL-33)-mediated recruitment of innate lymphoid type 2 cells (ILC2s). In susceptible individuals, this protective mechanism is impaired, resulting in elevated IL-33 production. Using a murine model of airway allergy, we found dectin-1 represses the induction of a distinct HDM-elicited epithelial cell population that co-express IL-33 and HIF-1a. Notably, HIF-1a is exclusively expressed by IL-33hi epithelial cells. It is known that allergen-induced IL-33 release from airway epithelium is due to elevation in oxidative stress, a known driver of HIF-1a activation. We found that HDM increases oxidative stress in the epithelium. Overexpressing dectin-1 in human bronchial epithelial cells blocks this by elevating glutathione (GSH) levels, a vital cellular antioxidant. Thus, dectin-1 signaling inhibits HDM-induced cellular oxidative stress. Accordingly, epithelial dectin-1 signaling represses HIF1A mRNA and prevents HIF-1a activity, as measured by assessing hypoxia-response element (HRE) activity. Therefore, we propose that epithelial dectin-1 signaling inhibits the release of IL-33 by suppressing oxidative stress and subsequent HIF-1a activation. Funding Sources Supported by NIHR01AI127644. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)