甲状腺荷尔蒙抗炎效果及机制研究

The NLRP3 inflammasome is crucial in innate immune response and inflammatory activation, and is responsible for a series of human major diseases like gout、type 2 diabetes and atherosclerosis, so it is important to study its activation and regulation mechanisms. Previous we found exogenous Omega-3 fatty acids could prevent type 2 diabetes by inhibiting the activation of NLRP3 inflammasome (Yan et al., 2013, Immunity); later, we found endogenous neurotransmitter dopamine could inhibit systemic inflammation through inhibition of NLRP3 inflammasome (Yan et al., 2015, Cell), but the activation and regulation network of NLRP3 inflammasome is still not quite clear. Preparatory work showed that thyroid hormone T4 could effectively inhibit NLRP3 inflammasome activation. In this study, we will further investigate the role of thyroid hormone in anti-inflammatory response and clarify the mechanisms. Furthermore, we will study how thyroid hormone affects peripheral system inflammation and metabolic disorder using LPS-induced septic shock model and high-fat food-induced type 2 diabetes model. This study is helpful to understand the activation mechanisms of inflammasome, and also may provide new target or strategy for therapy of inflammasome-related diseases.

NLRP3炎症小体与痛风、二型糖尿病、动脉粥样硬化等多种人类重大疾病密切相关，因此探究其活化和调控机制具有重要意义。我们近期工作发现，神经递质多巴胺和Omega-3不饱和脂肪酸都可以通过抑制NLRP3炎症小体干预炎症性疾病的发生发展（Yan et al., 2013, Immunity；Yan et al., 2015, Cell)，但是炎症小体的调控机制还需进一步探究。前期我们通过化合物文库筛选的方法发现甲状腺荷尔蒙T4可以抑制NLRP3炎症小体的活化，本课题将以此为基础探究甲状腺荷尔蒙抑制NLRP3炎症小体的作用及机制，并利用二型糖尿病等炎症小体相关动物模型探讨甲状腺荷尔蒙对炎症小体抑制作用的疾病相关性。该项目不仅有助于了解炎症小体的活化和调控机制，也能为炎症小体相关疾病提供治疗靶点和思路。

天然免疫系统通过模式识别受体识别病原和危险信号，启动炎症反应，以保护机体。模式识别受体家族的一些成员可以作为感知分子，与接头蛋白ASC和caspase-1前体蛋白形成多聚蛋白复合物，称为炎症小体。当感知到病原或危险信号时，炎症小体会组装、活化，促进IL-1β和IL-18的成熟和分泌，进一步促进炎症反应。炎症小体的过度活化会导致大量细胞因子产生，引发炎症性疾病的发生，如二型糖尿病、痛风、肿瘤等。因此，寻找调控炎症小体的内源性机制具有十分重要的意义。我们发现，甲状腺荷尔蒙T4可以显著地抑制MSU、Nigericin、ATP活化的NLRP3炎症小体，对转染LPS诱导的非经典炎症小体活化也有抑制作用。同时，T4还可以很好地抑制poly（A:T）活化的AIM2炎症小体，一定程度上对沙门氏菌诱导的NLRC4炎症小体也有抑制效果。此外，我们发现，T4通过抑制ASC多聚抑制了炎症小体活化；其类似物以及T3同样具有抑制炎症小体活化的作用。综上，我们的工作寻找到了一种具有抑制炎症小体活化作用的内源性小分子——甲状腺激素，并解释了甲状腺激素的抗炎机制。