Department of Hepatology, Taian Hospital of Traditional Chinese Medicine, Taian, 271000, People's Republic of China.
Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, People's Republic of China.
J Transl Med. 2021 Jun 12;19(1):258. doi: 10.1186/s12967-021-02812-7.
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.
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.
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.
Collectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma.
哮喘是一种常见的呼吸道疾病，其发病率在全球范围内呈上升趋势。气道炎症和重塑是哮喘发生的重要因素。我们进行这项研究旨在探讨组蛋白去乙酰化酶 4（HDAC4）介导的 Kruppel 样因子 5（KLF5）/Slug/CXC 趋化因子配体 12（CXCL12）轴对气道炎症和重塑调节中哮喘发生的影响。
通过卵清蛋白（OVA）灌洗诱导哮喘大鼠模型，通过 RT-qPCR 和 Western blot 检测肺组织中 HDAC4、KLF5、Slug 和 CXCL12 的表达。OVA 也用于诱导人 BEAS-2B 和 HBE135-E6E7 支气管上皮细胞的哮喘细胞模型。通过乙酰甲胆碱激发试验和 ELISA 检测模型小鼠气道高反应性（AHR）和炎症细胞因子表达。通过失活和过表达方法检测哮喘模型支气管平滑肌细胞（BSMC）的生物学行为。还通过免疫沉淀（IP）测定、双荧光素酶基因报告测定和染色质免疫沉淀（ChIP）检测 HDAC4、KLF5、Slug 和 CXCL12 之间的相互作用。
HDAC4 在 OVA 诱导的哮喘小鼠肺组织中上调，抑制 HDAC4 可减轻气道炎症和重塑。HDAC4 通过去乙酰化增加 KLF5 的转录活性；去乙酰化的 KLF5 与 Slug 的启动子结合，转录上调 Slug 表达，进而增加 CXCL12 的表达，促进支气管上皮细胞炎症，从而诱导 BSMC 的增殖和迁移。
综上所述，HDAC4 去乙酰化 KLF5 上调 Slug 和 CXCL12，导致气道重塑并促进哮喘进展。
