Th17细胞调控哮喘伴抑郁患者激素敏感性机制研究

It has been proposed that asthma with depression is associated with poor disease control and steroid-insensivity, but the underlying mechanisms is still unclear. Recent studies have confirmed that Th17 cells play an important role in decreasing steroid sensitivity in patients with asthma. Our previous study found that patients of asthma with depression was associated with overexpression of RORC mRNA and IL-17A levels. Thus, we hypothesized that asthma with depression is associated with hyperactivity of Th17 cells, which lead to steroid-insensivity through activating the hypothalamic-pituitary-adrenal (HPA) axis, and altering the expression levels of different subtypes of glucocorticoid receptor (GR) and the activity of HDAC2. Firstly, we aim to investigate the production of Th17-associated cytokines IL-7A in culture, the activation level of HPA axis, and the expression levels of GRα and GRβ and the activity of HDAC2 in patients of asthma with depression. Secondly, we will explore the relationships between Th17 cells and the characteristics of asthma, such as airway inflammation and airway hyperresponsiveness, or depression-like behavior in mice. Thirdly, we will investigate the role of IL-17A in changing the steroid-sensitivity in asthma with depression. Our study will firstly elucidate the molecular mechanisms of Th17 cell in asthma with depression and provide evidence for the therapeutic development.

哮喘伴抑郁患者病情控制差，激素治疗效果欠佳，是亟需解决的临床难题。本课题组前期研究发现，哮喘伴抑郁患者RORC mRNA和细胞因子IL-17A表达增高。我们假设，哮喘伴抑郁患者IL-17A过度分泌，激活下丘脑-垂体-肾上腺（HPA）轴、改变糖皮质激素受体（GR）亚型以及HDAC2活性,导致激素敏感性下降。本研究拟在检测受试者外周血Th17细胞转录因子与细胞因子表达水平的基础上，分析HPA轴激活水平、GRα和GRβ表达量以及HDAC2表达活性，研究Th17细胞对哮喘伴抑郁患者激素敏感性的调节作用。建立动物模型，研究实验动物脑组织和外周Th17细胞表达水平与疾病特征（如气道高反应性、行为学改变）的关系，并通过地塞米松干预试验，明确IL-17A对哮喘伴抑郁患者激素敏感性的调控作用及机制。研究结果将首次阐述Th17细胞调控哮喘伴抑郁患者激素敏感性的分子机制，为探寻新的治疗靶点提供理论依据。

哮喘伴抑郁患者病情控制差，激素治疗效果欠佳，是亟需解决的临床难题。研究表明，哮喘患者对激素的敏感性与 Th17 细胞及其分泌的细胞因子IL-17A 有关，研究哮喘伴抑郁患者是否具有激素抵抗型哮喘患者的免疫特征，以及对Th17细胞参与疾病机制的研究有望成为寻找新的有效治疗的突破口。本研究明确了哮喘伴抑郁患者存在Th17细胞与细胞因子异常表达，进一步通过细胞干预实验，明确Th17对哮喘伴抑郁患者激素敏感性的调节作用。通过建立疾病模型，探索哮喘伴抑郁肺区域、中枢神经系统及系统Th17细胞免疫特征，进一步给予抗IL-17A 单克隆抗体干预，探索Th17细胞及细胞因子IL-17A 在哮喘伴抑郁中的作用。本研究的结果对于阐述 Th17 细胞调控哮喘伴抑郁患者激素敏感性的机制，以及探寻新的治疗靶点提供了理论依据。