CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma.
CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma.
复制标题
在香烟烟雾暴露诱发的哮喘中，CpG寡脱氧核苷酸通过恢复组蛋白去乙酰化酶2来减弱RORγt介导的Th17细胞应答。
DOI：
10.1186/s13578-021-00607-3
复制
发表时间：
2021-05-20
影响因子：
7.5
通讯作者：
Zhang T
中科院分区：
文献类型：
--
作者：
Li H;Ye Q;Lin Y;Yang X;Zou X;Yang H;Wu W;Meng P;Zhang T
香烟烟雾(CS)暴露增加了与Th17表型增加相关的皮质类固醇不敏感哮喘，CS相关性哮喘需要新的治疗策略。组蛋白脱乙酰基酶2(HDAC2)存在于呼吸道上皮细胞中，对改善糖皮质激素不敏感起关键作用。我们最近证实了CpG寡核苷酸(CpG-ODN)对CS暴露哮喘的抗炎作用。然而，CpG-ODN对HDAC2表达和酶活性的影响尚不清楚。本研究旨在评估CpG-ODN是否通过依赖HDAC2的机制对CS诱导的哮喘中过度的Th17免疫反应起到保护作用，并与皮质类固醇的作用进行比较。采用哮喘模型及体外培养的支气管上皮细胞(HBE)，观察CpG-ODN单独及与布地奈德(BUD)合用对哮喘小鼠气道炎症及Th2/Th17相关免疫应答的影响。在小鼠肺标本和HBE细胞中也检测了HDAC2和维甲酸相关的孤儿核受体t(RORT)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、气道高反应性以及通过诱导HDAC2表达/活性来阻断RORT介导的Th17炎症，在体内协同减轻CS暴露的哮喘反应。在体外，CpG-ODN与BUD协同作用，在OVA和CSE攻击的HBE细胞中抑制Th17细胞因子的产生，同时抑制RORT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诱导的哮喘小鼠和CSE诱导的HBE细胞对糖皮质激素治疗的敏感性。CpG-ODN的这种作用可能与通过RORT/IL-17途径调节HDAC2的恢复有关，提示CpG-ODN可能是一种潜在的皮质类固醇节约剂，用于治疗具有Th17偏向免疫状态的CS诱导的哮喘。网上版载有补充材料，可在10.1186/s13578-021-00607-3查阅。
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 t (RORt) 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 RORt-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 RORt 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 RORt/IL-17 pathway regulation, suggesting that CpG-ODNs are potential corticosteroid-sparing agents for use in CS-induced asthma with Th17-biased immune conditions. The online version contains supplementary material available at 10.1186/s13578-021-00607-3.
登录
查看更多内容
影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
组蛋白脱乙酰基酶2介导的糖皮质激素受体的脱乙酰基化可以抑制NF-kappab。
影响因子：
15.3
作者：
Ito, Kazuhiro;Yamamura, Satoshi;Essilfie-Quaye, Sarah;Cosio, Borja;Ito, Misako;Barnes, Peter J;Adcock, Ian M
通讯作者：
Adcock, Ian M
CpG寡脱氧核苷酸纳米药物用于预防或治疗癌症，传染病和过敏。
影响因子：
8
作者：
Hanagata N
通讯作者：
Hanagata N
影响因子：
30.5
作者：
Manel, Nicolas;Unutmaz, Derya;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
10
作者：
Essilfie, Ama-Tawiah;Horvat, Jay C.;Hansbro, Philip M.
通讯作者：
Hansbro, Philip M.