HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation

Wendi Wei,Weida Chen,Naifeng He

doi:10.1186/s12967-021-02812-7

Abstract

BackgroundAsthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. We conducted this study aiming at exploring the effect of Histone deacetylase 4 (HDAC4)-mediated Kruppel-like factor 5 (KLF5)/Slug/CXC chemokine ligand-12 (CXCL12) axis on the development of asthma in regulation of airway inflammation and remodeling.MethodsAn asthmatic rat model was induced by ovalbumin (OVA) irrigation, and determined HDAC4, KLF5, Slug, and CXCL12 expression in the lung tissues by RT-qPCR and Western blot assay. OVA was also used to induce a cell model of asthma in human BEAS-2B and HBE135-E6E7bronchial epithelial cells. The airway hyperresponsiveness (AHR), and expression of inflammatory cytokines in model mice were examined using methacholine challenge test and ELISA. The biological behaviors were measured in asthma model bronchial smooth muscle cells (BSMCs) following loss- and gain- function approaches. The interactions between HDAC4, KLF5, Slug, and CXCL12 were also detected by IP assay, dual luciferase gene reporter assay, and ChIP.ResultsHDAC4 was upregulated in lung tissues of OVA-induced asthmatic mice, and inhibition of HDAC4 alleviated the airway inflammation and remodeling. HDAC4 increased KLF5 transcriptional activity through deacetylation; deacetylated KLF5 bound to the promoter of Slug and transcriptionally upregulated Slug expression, which in turn increased the expression of CXCL12 to promote the inflammation in bronchial epithelial cells and thus induce the proliferation and migration of BSMCs.ConclusionCollectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma.

Highlights

Asthma is a frequently occurring respiratory disease with an increasing incidence around the world
Taking the aforementioned reports into consideration, we propose a hypothesis in this study that Histone deacetylase 4 (HDAC4)-mediated Kruppel-like factor 5 (KLF5)/Slug/ CXC chemokine ligand-12 (CXCL12) axis should affect the development of asthma
Inhibition of HDAC4 attenuates airway inflammation and remodeling in asthmatic mice To study the role of HDAC4 in asthma, the si-HDAC4-1 and si-HDAC4-2 was transduced in human bronchial epithelial cells BEAS-2B and HBE135-E6E7 (HBE) and the silencing efficiency of HDAC4 was examined by RT-qPCR and Western blot assay; since sh-HDAC4-2 showed the best silencing efficiency (Fig. 1a, b), it was packaged into lentivirus for subsequent experimentation

Summary

Introduction

Asthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. Asthma is regarded as the most common chronic respiratory disease, an affects people of all ages [1]. Asthma is understood to be a complicated genetic disease, which is strongly affected by environmental factors; its increasing incidence brings a great social burden due to morbidity, loss of quality of life, and medical. Asthma is featured by airway inflammation, hyperresponsiveness to antigens, as well as remodeling [4]. Bronchial smooth muscle cells (BSMCs) can proliferate and release cytokines, thereby resulting in the occurrence of asthma [5]. Obtaining a better understanding of the mechanisms involved in airway inflammation and BSMC proliferation is critical for the better treatment of asthma

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