Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation
Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation
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多巴胺利用 DRD5-ARRB2-PP2A 信号轴阻断 TRAF6 介导的 NF-kappa B 通路并抑制全身炎症
DOI：
10.1016/j.molcel.2020.01.022
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发表时间：
2020-04-02
期刊：
影响因子：
16
通讯作者：
Yang, Shuo
中科院分区：
文献类型：
--
作者：
Wu, Yuqing;Hu, Yingchao;Yang, Shuo
神经递质多巴胺（DA）对炎症作用的功能相关性和机制基础尚不清楚。本研究发现，DA通过DRD5受体抑制tlr2诱导的巨噬细胞NF-kappa B活化和炎症。我们发现DRD5受体分别通过其CT环和IC3环中的EFD和IYX(X)I/L基序，可以直接招募TRAF6及其负调节因子ARRB2，形成一个多蛋白复合物，该复合物也含有下游信号蛋白，如TAK1、IKKs和PP2A，从而损害TRAF6介导的NF-kappa B的激活和促炎基因的表达。此外，DA- drd5 - arrb2 - pp2a信号轴可以预防金黄色葡萄球菌诱导的炎症，并在DA治疗后保护小鼠免受金黄色葡萄球菌诱导的脓毒症和脑膜炎。总的来说，这些发现首次证明了DA-DRD5信号可以控制炎症，并详细描述了其潜在机制，并确定DRD5-ARRB2-PP2A轴是未来治疗炎症相关疾病（如脑膜炎和败血症）的潜在靶点。
The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-kappa B activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-kappa B and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis.