Abstract
BackgroundAsthma is a heterogeneous chronic inflammatory disease of the airway, involving reversible airflow limitation and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is limited understanding of the signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to investigate if the Yes-associated protein (YAP)/hypoxia inducible factor-1α (HIF-1α)/microRNA-182 (miR-182)/early growth response 2 (EGR2) axis is involved in mediating Th17 cell differentiation and disease severity in asthma.MethodsThe study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin-induced murine asthma models, and mouse naive CD4+ T cells. The subpopulation of Th17 cells was examined by flow cytometry. The levels of interleukin-17A were determined by enzyme linked immunosorbent assay. Chromatin immunoprecipitation-quantitative polymerase chain reaction assays and dual-luciferase reporter gene assays were performed to examine interactions between HIF-1α and miR-182, and between miR-182 and EGR2.ResultsYAP, HIF-1α, and miR-182 were upregulated but EGR2 was downregulated in human and mouse peripheral blood mononuclear cells from the asthma group. 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 overexpression of EGR2 countered the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction.ConclusionThese results indicate that activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, thus suggesting a potential therapeutic target for asthma.
Highlights
Asthma is a heterogeneous chronic inflammatory disease of the airway, involving reversible airflow limitation and airway remodeling
Using the hTFtarget tool YAP1 was found to target the HIF1A gene (Additional file 1: Fig. S1E). Based on these aforementioned in silico analyses and previous experimental data, we hypothesized that YAP1 (YAP) may affect the development of asthma through regulation of HIF1A (HIF-1α), and designed the current study in order to validate this assumption
Asthma mice treated with oe-Yes-associated protein (YAP), oe-hypoxia inducible factor-1α (HIF-1α), or miR-182 mimic presented with reduced high-density lipoprotein cholesterol (HDL-C) levels, while increased HDL-C levels were found in response to early growth response 2 (EGR2) overexpression (p < 0.05; Additional file 5: Fig S5B). These findings indicated that the overexpression of EGR2 alleviated the exacerbated asthma and lipid metabolism dysfunction evoked by YAP/HIF-1α/miR-182 signaling in vivo
Summary
Asthma is a heterogeneous chronic inflammatory disease of the airway, involving reversible airflow limitation and airway remodeling. The aim of this study was to investigate if the Yes-associated protein (YAP)/hypoxia inducible factor-1α (HIF-1α)/microRNA-182 (miR-182)/early growth response 2 (EGR2) axis is involved in mediating Th17 cell differentiation and disease severity in asthma. Early growth response 2 (EGR2), known as a transcription factor negatively regulating T-cell activation [19], has been reported to reduce Th17 cell differentiation [20] In another instance, a reduction of high-density lipoprotein cholesterol (HDL-C) has been linked to increased numbers of Th17 cells [21]. We sought to determine if YAP and HIF-1α function through a pathway that involves low HDL-C-induced increased Th17 cells in the pathogenesis of pediatric asthma These results could potentially reveal a hitherto undocumented link between HIF-1α, miR-182, EGR2, and Th17 cells in context of asthma and we investigated if miR-182 and EGR2 were involved in asthma pathogenesis
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