miR-146调控Th17细胞分化异常参与自身免疫性甲状腺炎相关抑郁症发生的机制研究

Population-based study found that patients with autoimmune thyroiditis (AIT) easy to merge depression, its pathogenesis might be related to abnormal correlation Th17 differentiation. Th17 plays an important role in the pathogenesis of autoimmune diseases. Micro-RNA (miRNA) is important in regulation of immune cells differentiation. Therefore we mean to study the expression of miRNA-146 regulated Th17 cell differentiation in the pathogenesis of autoimmune thyroiditis related depression occurs. In our AIT mice models，we found elevated thyroid autoantibodies is positively correlated with depression behaviors, IL-1β and other related cytokines are high expression as well. In this study we aim to establish AIT mouse models and research miRNA-146 regulates Th17 cell differentiation in the pathogenesis of autoimmune thyroiditis concomitant with depression. mTg immune in CBA/J female mouse established AIT mouse model, after given environmental stress depression-like behaviors were evaluated by ethology experiments. SPECT cerebral angiogram was measured to assess brain perfusion by 99mTC tail intravenous injection in each group. Research the expression of miRNA-146 in serum, thyroid, spleen and brain. we determinate the Th17 cell subgroup ratio in brain and spleen； and investigated whether miRNA-146 take part in the developing AIT related depression by regulating the differentiation and function of Th17,confirming possible targets PPAR and RORt for regulating Th17.Overexpression of miRNA-146 by injecting lentiviral vector in depression behavior positive group, aiming to observe the changes of the behaviors ,brain perfusion and key targets of Th17 cell differentiation signaling pathway. This study will provide a theoretical basis for future target therapeutic strategies.

人群研究发现自身免疫性甲状腺炎（AIT）的患者易合并抑郁症，其发病机制可能与Th17分化异常存在相关性。miRNA-146是调节自身免疫反应的重要miRNA，拟在AIT小鼠模型中研究miRNA-146调控Th17细胞分化异常参与AIT相关抑郁症发生的发病机制。前期研究在AIT小鼠模型中发现甲状腺自身抗体升高与抑郁行为存在正相关，同时抑郁小鼠存在IL-1β等细胞因子水平升高。mTg免疫CBA/J雌鼠，建立动物模型，给予环境应激刺激后通过抑郁相关的行为学实验评估各组小鼠的抑郁行为倾向； SPECT脑血管造影，观察各组小鼠脑血流分布情况；研究各组小鼠miRNA146在脑组织，甲状腺和脾脏中的表达水平；测定脑内及脾脏Th17细胞的亚群比例，测定Th17细胞分化通路中的关键分子PPAR和 RORt及下游相关细胞因子的水平。miRNA-146过表达后再次检测上述指标，验证假说。

背景研究发现自身免疫性甲状腺炎（autoimmune thyroiditis，AIT）的患者更容易罹患抑郁症，免疫调节异常在这类疾病的发生发展中起到了重要的作用，本研究拟在AIT的NOD.H-2h4小鼠模型中，探讨miRNA-146通过调控Th17细胞分化参与AIT相关抑郁症发生的机制。本研究揭示了：1）自身免疫性甲状腺炎的NOD.H-2h4小鼠在慢性不可遇见性轻度应激的刺激下较正常小鼠更易出现抑郁行为（包括在旷场实验，悬尾实验及强迫游泳实验中均表现出明显差异）；同时测定额叶皮质五羟色胺（5-TH）的水平较正常小鼠浓度减少。2）AIT合并抑郁行为小鼠脑皮质内及甲状腺组织内miR-146水平、脾脏组织内Th17细胞的亚群比例较正常小鼠显著升高，其上下游的炎症介质（IL-17,IL-22,IL-6及IL-1beta）的水平也较正常小鼠显著升高。3）通过检测大脑皮质中RORgammat的水平，研究初步证实miR-146可通过上调RORgammat的水平调控Th17的分化程度。本研究较为新颖的提出了miR-146通过上调RORgammat的水平调控Th17的分化，参与了自身免疫性甲状腺炎合并抑郁症的发生，为此类疾病的研究拓宽了思路，并对疾病的治疗提供了可能的靶点。