儿茶酚胺对类风湿性关节炎Treg/Th17失衡的作用及其受体信号转导机制

We have previously reported that catecholamines facilitate a shift of differentiation and function of CD4+ T cells from type 1-helper T (Th1) cells toward Th2. However, effects of catecholamines on regulatory T (Treg) cells and Th17 cells, the two new subpopulations of CD4+ T cells that have been considered closely associated with rheumatoid arthritis (RA), an autoimmune disease, still remain to be clarified. In our pre-experiments, we found that an imbalance with Treg impairment and Th17 enhancement occurred in collagen-induced arthritis (CIA), a mouse model of RA. In this program, we first explore effects of chatecolamines (norepinephrine, NE, and epinephrine, E) on differentiation and function of Treg and Th17 cells and on expression of G-protein coupled receptor kinase-2 (GRK2) and internalization of G-protein coupled receptors (GPCRs) in these cells, and also investigate GPCR-downstream signal-transduction mechanisms underlying these catecholamine effects, including cAMP/PKA/CREB, PLC/IP3/Ca2+ and mitogen-activated protein kinase (MAPK) pathways. Through this exploration, we show that because of these changes in GRK2 expression, GPCR internalization and MAPK signaling in response of Treg and Th17 cells to NE and E in CIA progression, NE and E aggravate Treg/Th17 imbalance of CIA. Subsequently, we use gene intervening approach to reveal that either the overexpression of GRK2 gene or the knockdown of MAPK gene in Treg cells impairs the inhibitory effect of NE and E on Treg cells. Lastly, we adoptively transfer Treg cells that have been overexpressed with GRK2 gene or interfered with MAPK gene to CIA mice to present that these therapic measures correct Treg/Th17 imbalance, suppress chronic inflammation, and alleviate CIA. Thus, this study extends our understanding of pathogenesis of autoimmune diseases such as RA and provides new targets for therapeutic strategy of these diseases.

我们已报道儿茶酚胺调节CD4+T细胞的分化及功能，但儿茶酚胺对Treg和Th17这两类新近认为与类风湿性关节炎密切相关的CD4+T细胞亚群的作用不清楚。我们预实验显示胶原诱导性关节炎（CIA，类风湿性关节炎的小鼠模型）出现Treg减弱/Th17增强的失衡。本项目首先探讨儿茶酚胺（去甲肾上腺素，NE和肾上腺素，E）对CIA的Treg和Th17细胞的分化和功能的影响及其受体信号机制，阐明由于CIA中Treg和Th17的GPCRs内吞和MAPK信号等发生了改变，因此NE和E可加重CIA的Treg/Th17失衡。然后，通过基因干预方法说明CIA的Treg细胞内GRK2过表达或MAPK沉默可减弱NE和E对Treg的抑制。最后将GRK2过表达或MAPK沉默的Treg细胞输入CIA体内，表明这些措施能纠正Treg/Th17失衡及治疗CIA。为类风湿性关节炎等自身免疫性疾病的发病机制及治疗策略提供新资料。

研究背景和内容：机体内儿茶酚胺包括去甲肾上腺素（norepinephrine, NE）、肾上腺素（epinephrine, E）和多巴胺（dopamine, DA）。我们已经报道，儿茶酚胺（包括NE、E和DA）对T淋巴细胞功能具有明显的调节作用。但在疾病状态下，儿茶酚胺对T细胞的作用仍知之甚少。类风湿性关节炎是一种慢性自身免疫性疾病，已有研究说明，T细胞中Th17/Treg失衡是类风湿性关节炎的重要致病因素。因此，本项目以Th17/Treg失衡为靶点，利用类风湿性关节炎的最佳动物模型之一胶原诱导性关节炎（collagen-induced arthritis, CIA）探索儿茶酚胺对类风湿性关节炎的作用及其受体信号转导机制。.重要结果和数据：① NE和E都抑制了CIA的CD4+ T细胞向促炎性的Th17细胞分化，并减弱了Th17细胞的功能；NE和E都促进了CIA的CD4+ T细胞向免疫抑制性的Treg细胞分化，并增强了Treg细胞的功能。② NE和E主要通过激活β2-肾上腺素受体减轻了CIA的Th17/Treg失衡，改善了CIA的关节炎症和关节病理变化。③ G蛋白耦联受体（G-protein-coupled receptors, GPCRs）下游的经典途径（cAMP-PKA）及新兴途径（β-arrestin-MAPK/ERK）均可介导NE和E的上述作用，并且这两条信号途径之间有交互抑制作用。④ CIA小鼠踝关节内注射酪氨酸（tyrosine hydroxylase, TH）基因过表达载体减轻了Th17细胞的炎性反应及CIA的病理改变和症状，而CIA小鼠踝关节内注射TH基因沉默载体加重了Th17细胞的炎性反应及CIA的病理改变和症状。⑤ 将过表达β-arrestin2的Treg细胞过继转移给CIA小鼠，可减轻CIA小鼠的Th17/Treg失衡，并改善动物的关节炎症和关节病理变化。.科学意义：以神经内分泌免疫调节的视角，并以Th17/Treg失衡为切入点，我们说明了儿茶酚胺介质对类风湿性关节炎具有缓解作用，并且揭示了儿茶酚胺的这种作用由β2-肾上腺素受体及GPCRs经典的和新兴的信号通路介导。这些原创性的结果拓宽和加深了我们对类风湿性关节炎致病机制的认识和理解，也为临床上设计治疗类风湿性关节炎的新策略提供新的理念和潜在的作用靶点。

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