The YAP/HIF-1α/miR-182/EGR2 Axis is Implicated in Asthma Severity by Control of Th17 Cell Differentiation
Abstract Background: Asthma is a heterogeneous chronic inflammatory disease of the airways, with reversible airflow limitations and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is hitherto little data about signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to ascertain whether the YAP/HIF-1α/miR-182/EGR2 axis underpins Th17 cell differentiation and asthma severity.Methods: The study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin (OVA)-induced murine asthma models, and mouse naive CD4+ T. The subpopulation of Th17 cells was examined by flow cytometry. The level of IL-17A was determined by ELISA method. ChIP-qPCR assay and dual-luciferase reporter gene assay were performed to examine interaction between HIF-1α and miR-182, miR-182 and EGR2.Results: YAP, HIF-1α, and miR-182 were found to be up-regulated but EGR2 was down-regulated in human and mouse peripheral blood mononuclear cells (PBMCs) in the context of asthma. Abundant expression of YAP and HIF-1α promoted miR-182 expression and then inhibited EGR2, a target of miR-182, thus enhancing Th17 differentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo findings revealed that over-expression of EGR2 undermined the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction.Conclusion: These results shed light on that the activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, providing a potential therapeutic target in asthma.