Li Hongtao, Ye Qimei, Lin Yusen, Yang Xuena, Zou Xiaoling, Yang Hailing, Wu Wenbin, Meng Ping, Zhang Tiantuo
Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, People's Republic of China.
Cell Biosci. 2021 May 20;11(1):92. doi: 10.1186/s13578-021-00607-3.
Cigarette smoke (CS) exposure increases corticosteroid insensitive asthma related to increased Th17 phenotype, and new treatment strategies are needed for CS-associated asthma. Histone deacetylase 2 (HDAC2), found in the airway epithelium, is critical for ameliorating glucocorticoids insensitivity. We recently demonstrated the anti-inflammatory effects of CpG oligodeoxynucleotides (CpG-ODNs) on CS-exposure asthma. However, the effects of CpG-ODNs on HDAC2 expression and enzymatic activity remain unclear. This study aimed to assess whether CpG-ODNs protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms and compared their effects with those of corticosteroids.
The effects of CpG-ODNs alone and in combination with budesonide (BUD) on airway inflammation and Th2/Th17-related airway immune responses were determined using an in vivo model of CS-induced asthma and in cultured bronchial epithelial (HBE) cells administered ovalbumin (OVA) and/or cigarette smoke extract (CSE). HDAC2 and retinoid-related orphan nuclear receptor γt (RORγt) expression were also assessed in mouse lung specimens and HBE cells.
CpG-ODNs and BUD synergistically attenuated CS exposure asthmatic responses in vivo by modulating the influx of eosinophils and neutrophils, airway remodeling, Th2/Th17 associated cytokine and chemokine production, and airway hyperresponsiveness and blocking RORγt-mediated Th17 inflammation through induced HDAC2 expression/activity. In vitro, CpG-ODNs synergized with BUD to inhibit Th17 cytokine production in OVA- and CSE-challenged HBE cells while suppressing RORγt and increasing epithelial HDAC2 expression/activity.
CpG-ODNs reversed CS-induced HDAC2 downregulation and enhanced the sensitivity of CS-exposed asthmatic mice and CSE-induced HBE cells to glucocorticoid treatment. This effect may be associated with HDAC2 restoration via RORγt/IL-17 pathway regulation, suggesting that CpG-ODNs are potential corticosteroid-sparing agents for use in CS-induced asthma with Th17-biased immune conditions.
接触香烟烟雾（CS）会增加与Th17表型增加相关的皮质类固醇不敏感型哮喘，因此需要新的治疗策略来治疗与CS相关的哮喘。气道上皮中发现的组蛋白脱乙酰基酶2（HDAC2）对于改善糖皮质激素不敏感性至关重要。我们最近证明了CpG寡脱氧核苷酸（CpG-ODN）对CS暴露型哮喘具有抗炎作用。然而，CpG-ODN对HDAC2表达和酶活性的影响仍不清楚。本研究旨在评估CpG-ODN是否通过HDAC2依赖性机制预防CS诱导的哮喘中过度的Th17免疫反应，并将其与皮质类固醇的作用进行比较。
使用CS诱导的哮喘体内模型以及用卵清蛋白（OVA）和/或香烟烟雾提取物（CSE）处理的培养支气管上皮（HBE）细胞，确定单独使用CpG-ODN以及与布地奈德（BUD）联合使用对气道炎症和Th2/Th17相关气道免疫反应的影响。还评估了小鼠肺标本和HBE细胞中HDAC2和视黄酸相关孤儿核受体γt（RORγt）的表达。
CpG-ODN和BUD通过调节嗜酸性粒细胞和中性粒细胞的流入、气道重塑、Th2/Th17相关细胞因子和趋化因子的产生以及气道高反应性，并通过诱导HDAC2表达/活性来阻断RORγt介导的Th17炎症，从而在体内协同减轻CS暴露哮喘反应。在体外，CpG-ODN与BUD协同抑制OVA和CSE刺激的HBE细胞中Th17细胞因子的产生，同时抑制RORγt并增加上皮HDAC2的表达/活性。
CpG-ODN逆转了CS诱导的HDAC2下调，并增强了CS暴露哮喘小鼠和CSE诱导的HBE细胞对糖皮质激素治疗的敏感性。这种作用可能与通过RORγt/IL-17途径调节恢复HDAC2有关，表明CpG-ODN是用于具有Th17偏向免疫状态的CS诱导哮喘的潜在糖皮质激素节省剂。
