The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell differentiation

Abstract

Background Asthma 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. Methods The 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. Results YAP, 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. Conclusion These 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.

hBMSC-derived Exosomes Mitigate Th17/Treg Homeostasis in Periodontitis via miR-1246

“…When the Hippo pathway is inactive, YAP1 is unphosphorylated and located in the nucleus; when the Hippo pathway is active, phosphorylated YAP1(S127) remains in the cytoplasm and mediates the expression of multiple downstream genes 42 . Our results suggested that lower expression of total YAP1 is associated with a lower Th17/Treg ratio, which is consistent with the nding of Zhou et al that abundant expression of YAP enhanced Th17 cell differentiation in patients with asthma exacerbation 43 .…”

Human Bone Marrow Mesenchymal Stem Cell-derived Extracellular Vesicles Restore Th17/Treg Homeostasis in Periodontitis via miR-1246

“…Activation of the Hippo pathway leads to the phosphorylation of YAP1; p-YAP1(S127) is located in the cytoplasm, where it mediates multiple downstream genes [41]. Our results suggested that lower expression of total YAP1 is associated with a lower Th17/Treg ratio, consistent with the ndings by Zhou et al [42] that abundant expression of YAP1 led to increased Th17 cell differentiation in patients with asthma exacerbation.…”

Immunometabolism in the pathogenesis of asthma

“…Prostacyclin (PGI2) is an end product derived from the sequential metabolism of AA via cyclooxygenase and PGI synthase, its analogs were discovered to suppress CD4+ T cell secretions of Th1 and IL‐33‐induced Th2 cytokines in a dose‐dependent pattern [39, 40], helping to reducing airway inflammation. Moreover, obese asthmatics frequently exhibit a Th17‐biased immune response [41], which is linked to Th17 cell differentiation under the aberrant lipid metabolism [42]. Inhibiting acetyl‐CoA carboxylase 1 can diminish the generation of Th17 cells while increasing the number of anti‐inflammatory Foxp3(+) Treg cells [43], which further confirms the contribution of abnormal lipid metabolism of CD4+ T cells in asthma inflammation.…”

“…Lipid metabolism can regulate CD4+ T cells differentiation and activation, whereas T cells can accumulate metabolites needed for lipid metabolism during activation. [34,42] Arachidonic acid can be transformed into leukotrienes (LTs) and prostaglandins (PGs), and leukotrienes can delay the apoptosis of eosinophils. Eosinophils producing cysLTs to act on the eosinophil adhesion and promote the eosinophils' migration to the lungs.…”