Xu Li, Sun Wen J, Jia Ai J, Qiu Lu L, Xiao Bing, Mu Lin, Li Jian M, Zhang Xiu F, Wei Yan, Peng Cong, Zhang Dong S, Xiang Xu D
1Department of the Second Thoracic Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine and Hunan Cancer Hospital, Central South University, 283 Tongzipo Road, Changsha, 410006 Hunan China.
2Department of Respiratory Medicine, Hunan Centre for Evidence-based Medicine, Research Unit of Respiratory Diseases, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011 Hunan China.
J Inflamm (Lond). 2018 Aug 20;15:15. doi: 10.1186/s12950-018-0191-x. eCollection 2018.
T helper 17 (Th17) cells have proven to be crucial in the pathogenesis of neutrophils-dominant asthma. Hypoxia inducible factor-1α (HIF-1α) is involved in allergic responses in asthma. Our previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) expression was increased in asthma patients. The aim of the present study is to understand how MBD2 interacts with HIF-1α to regulate Th17 cell differentiation and IL-17 expression in neutrophils-dominant asthma.
A neutrophils-dominant asthma mouse model was established using female C57BL/6 mice to investigate Th17 cell differentiation and MBD2 and HIF-1α expression regulation using flow cytometry, western blot or qRT-PCR. MBD2 and HIF-1α genes were silenced or overexpressed through lentiviral transduction to explore the roles of MBD2 in Th17 cell differentiation and IL-17 release in neutrophils-dominant asthma.
A neutrophilic inflammatory asthma phenotype model was established successfully. This was characterized by airway hyperresponsiveness (AHR), increased BALF neutrophil granulocytes, activated Th17 cell differentiation, and high IL-17 levels. MBD2 and HIF-1α expression were significantly increased in the lung and spleen cells of mice with neutrophils-dominant asthma. Through overexpression or silencing of MBD2 and HIF-1α genes, we have concluded that MBD2 and HIF-1α regulate Th17 cell differentiation and IL-17 secretion. Moreover, MBD2 was also found to regulate HIF-1α expression.
Our findings have uncovered new roles for MBD2 and HIF-1α, and provide novel insights into the epigenetic regulation of neutrophils-dominant asthma.
辅助性T细胞17（Th17）已被证明在以中性粒细胞为主的哮喘发病机制中起关键作用。缺氧诱导因子-1α（HIF-1α）参与哮喘的过敏反应。我们之前的研究表明，甲基化CpG结合域蛋白2（MBD2）在哮喘患者中的表达增加。本研究的目的是了解MBD2如何与HIF-1α相互作用，以调节以中性粒细胞为主的哮喘中Th17细胞的分化和白细胞介素-17（IL-17）的表达。
使用雌性C57BL/6小鼠建立以中性粒细胞为主的哮喘小鼠模型，通过流式细胞术、蛋白质免疫印迹法或定量逆转录聚合酶链反应（qRT-PCR）研究Th17细胞分化以及MBD2和HIF-1α的表达调控。通过慢病毒转导使MBD2和HIF-1α基因沉默或过表达，以探讨MBD2在以中性粒细胞为主的哮喘中Th17细胞分化和IL-17释放中的作用。
成功建立了嗜中性粒细胞性炎症哮喘表型模型。其特征为气道高反应性（AHR）、支气管肺泡灌洗（BALF）中性粒细胞增多、活化的Th17细胞分化以及高IL-17水平。在以中性粒细胞为主的哮喘小鼠的肺和脾细胞中，MBD2和HIF-1α表达显著增加。通过MBD2和HIF-1α基因的过表达或沉默，我们得出结论，MBD2和HIF-1α调节Th17细胞分化和IL-17分泌。此外，还发现MBD2调节HIF-1α的表达。
我们的研究结果揭示了MBD2和HIF-1α的新作用，并为以中性粒细胞为主的哮喘的表观遗传调控提供了新见解。
