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The YAP/HIF-1Α/Mir-182/EGR2 Axis Is Implicated in Asthma Severity

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The YAP/HIF-1Α/Mir-182/EGR2 Axis Is Implicated in Asthma Severity Zhou et al. Cell Biosci (2021) 11:84 https://doi.org/10.1186/s13578-021-00560-1 Cell & Bioscience RESEARCH Open Access The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell diferentiation Jing Zhou1, Ning Zhang2, Wei Zhang1, Caiju Lu1 and Fei Xu1* Abstract Background: Asthma is a heterogeneous chronic infammatory disease of the airway, involving reversible airfow 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 diferentiation 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 diferentia- tion 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 fow 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 expres- sion and then inhibited EGR2, a target of miR-182, thus enhancing Th17 diferentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo overexpression of EGR2 countered the promoting efect 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 difer- entiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, thus suggesting a potential therapeutic target for asthma. Keywords: YAP, HIF-1α, MiR-182, EGR2, Th17 cells, Diferentiation, Asthma, Dyslipidemia Background whereas asthma-related mortality is predictably higher Asthma is a frequently occurring disease of the airways, in lower-income countries [2]. Albeit the global preva- afecting about 300 million people worldwide [1]. Te lence of asthma is about 4–5%, this fgure can vary as incidence of asthma is higher in high-income countries, much as 21-fold across diferent countries [2]. Te well-recognized pathophysiology of asthma consists of recurrent lung epithelial infammation, bronchial *Correspondence: [email protected] 1 Department of Respiratory Medicine, The First Afliated Hospital smooth muscle hyperreactivity, chronic lung tissue of Nanchang University, No. 17, Yongwai Street, Donghu District, remodeling, and excessive mucus production, leading Nanchang 330006, People’s Republic of China to reversible airfow restriction [3]. Te vast majority Full list of author information is available at the end of the article of patients with asthma also present with concomitant © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhou et al. Cell Biosci (2021) 11:84 Page 2 of 17 rhinitis, which can further amplify the risk for devel- Results oping asthma with heightened bronchial hyperrespon- YAP, HIF‑1α and miR‑182 are upregulated and HDL‑C levels siveness and reactivity to a variety of stimuli [4]. Te are decreased in asthma current management of asthma primarily focuses on With an aim to identify the putative genes implicated in alleviating disease severity and choosing the appropri- the development of asthma, a diferential gene expression ate medical therapy to control symptoms and reduce analysis was performed on the asthma-related GSE27876 the risk of exacerbations; however, some patients still dataset retrieved from the Gene Expression Omnibus experience acute exacerbation of symptoms and a loss database (https:// www. ncbi. nlm. nih. gov/ gds) using the of disease control [5, 6], highlighting an urgent need to R package Limma (http:// www. bioco nduct or. org/ packa fully elucidate the underlying pathogenesis and develop ges/ relea se/ bioc/ html/ limma. html). Te GSE27876 data- more efcacious treatment regimens to better tackle set (comparing peripheral blood cells from mild and asthma [7]. severe asthma that were selected from patients clas- Recent data demonstrated that Yes-associated pro- sifed into the asthma treatment step 4, in accordance tein (YAP), a downstream target of the Hippo path- with the criteria described in the Global Initiative for way, is implicated in the generation and maintenance Asthma) was identifed. It comprised of 5 normal sam- of cancer-associated fbroblasts and vascular smooth ples and 10 asthma samples where peripheral blood was muscle cell diferentiation [8, 9]. YAP holds signifcant the sample type. With the selected cutof criteria (|log- potential as an anticancer immunotherapeutic target FoldChange|> 1.5, and p < 0.05), a total of 331 diferen- owing to the fact that YAP defciency induces dysfunc- tially expressed genes (DEGs) were identifed (Additional tional Tregs unable to suppress anti-tumor immunity fle 1: Fig. S1A, Additional fle 9: Table S1). In addition, or promote tumor growth [10]. Silencing YAP has been 318 human transcription factors were identifed from the shown to facilitate airway smooth muscle cell prolifera- Cistrome database (http:// cistr ome. org/). A Venn dia- tion, migration, and contraction induced by sphingo- gram analysis of the 331 DEGs and 318 human transcrip- sine-1-phosphate in asthma [11]. In addition, YAP can tion factors revealed 5 transcription factors were found at bind to hypoxia-inducible factor 1α (HIF-1α) and main- the intersection, namely H2AFX, NOTCH1, RUNX1T1, tain its protein stability, thus promoting hepatocellu- USF1, and YAP1 (Additional fle 1: Fig. S1B, Additional lar carcinoma cell glycolysis under hypoxic stress [12]. fle 10: Table S2). Subsequently, protein–protein interac- During the induction phase of asthma, treatment with tions (PPI) between these aforementioned 5 transcription HIF-1α inhibitor is shown to decrease eosinophilia in factors and their related genes were identifed using the bronchoalveolar lavage samples, lung parenchyma, and GeneMANIA web-based tool (http:// genem ania. org/). total lung infammation [13]. Moreover, HIF-1α has As illustrated in Additional fle 1: Fig. S1C and Table 1, also been shown to promote the expression of micro- the 2 most robustly related transcription factors were RNA-182 (miR-182) [14]. Tis is notable as miR-182 identifed as NOTCH1 and YAP1. YAP1 has been widely is also documented as upregulated during T-helper correlated with asthma [23, 24], and also known to infu- 17 (T17) cell diferentiation [15]. Accruing research ence disease progression by mediating HIF-1α in liver has revealed a signifcant correlation of activated T17 cancer and pancreatic cancer [12, 25]. As demonstrated cells with the progression of asthma [16–18]. Moreo- previously, NOTCH1 is involved in the promotion of ver, early growth response 2 (EGR2), known as a tran- the GATA3-mediated T2 response (immunity), which scription factor negatively regulating T-cell activation makes NOTCH1 an unlikely candidate responsible for [19], has been reported to reduce T17 cell diferentia- the non-T2 infammatory pattern in asthma [26]. As a tion [20]. In another instance, a reduction of high-den- result, YAP1 (YAP) was selected as the upstream gene sity lipoprotein cholesterol (HDL-C) has been linked for investigation in the current study. In addition, using to increased numbers of T17 cells [21]. In a related the Multi Experiment Matrix (MEM) web based tool fnding, decreased HDL-C levels have been found in (https:// biit. cs. ut. ee/ mem/ index. cgi) it was predicted that children with asthma [22]. Terefore, we sought to YAP1 was signifcantly co-expressed with HIF1A (Addi- determine if YAP and HIF-1α function through a path- tional fle 1: Fig. S1D). Using the hTFtarget tool (http:// way that involves low HDL-C-induced increased T17 bioin fo. life. hust. edu. cn/ hTFta rget#!/) YAP1 was found to cells in the pathogenesis of pediatric asthma. Tese target the HIF1A gene (Additional fle 1: Fig. S1E). Based results could potentially reveal a hitherto undocu- on these aforementioned in silico
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