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

Abstract

Background 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. 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. Methods An 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. Results HDAC4 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. Conclusion Collectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma.

The Role of Defective Epithelial Barriers in Allergic Lung Disease and Asthma Development

“…160 In a mouse model of ovalbumin (OVA)-induced asthma, HDAC4 was upregulated in the lung tissue. 161 We and others have also shown that inhibition of endogenous HDAC activity reconstitutes the defective barrier by increasing TJ expression. 55,159,[161][162][163] https://doi.org/10.2147/JAA.S324080…”

“…161 We and others have also shown that inhibition of endogenous HDAC activity reconstitutes the defective barrier by increasing TJ expression. 55,159,[161][162][163] https://doi.org/10.2147/JAA.S324080…”

Role of Histone Post-Translational Modifications in Inflammatory Diseases

“…HDAC2 protein expression could be reduced by cigarette smoke exposure via enhancing AKT signaling, and it can be reversed by roxithromycin (RMX) treatment to increase HDAC2 expression and reduce airway inflammation ( 159 ). The expression of HDAC4 was upregulated in lung tissues of asthmatic mice, and it could deacetylate Kruppel-like factor 5 (KLF5) to upregulate Slug and CXC chemokine ligand-12 (CXCL12), thus triggering airway remodeling and promoting progression of asthma ( 26 ). Overexpression of SIRT6 reduced cell migration and proliferation, suppressed the activation of Smad3 phosphorylation induced by TGF-β1 treatment, and at the same time decreased the H3K9 acetylation level and the transcriptional activity of the c-Jun promoter ( 160 ).…”

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

“…The association of these transcription factors with asthma was demonstrated. For example, histone deacetylase 4 can mediate KLF5 deacetylation to upregulate CXCL12, leading to airway remodeling and promoting the progression of asthma ( 42 ).…”