β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia
β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia
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DOI：
10.1038/cdd.2013.152
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发表时间：
2014-03-01
影响因子：
12.4
通讯作者：
Wei, L-N
中科院分区：
文献类型：
--
作者：
Feng, X.;Wu, C-Y;Wei, L-N
小胶质细胞的激活加剧了神经元的丧失，并导致了帕金森病（PD）等进行性神经系统疾病。这种炎症进展是由促啡肽（Dyn）对抗的，促啡肽是kappa-阿片受体（KOR）的内源性配体。我们发现，小胶质细胞β -抑制素介导Dyn/KOR限制内毒素诱导的促炎效应物和细胞因子的产生，从而保护神经元免受炎症诱导的神经毒性。激动剂激活的KOR增强了β -arrestin2与转化生长因子- β -活化激酶1 （TAK1）结合蛋白1 （TAB1）的相互作用，破坏了TAK1-TAB1介导的促炎基因表达。我们揭示了β -抑制素在神经保护中的一个新的生理作用，通过受体内化触发小胶质炎性神经毒性信号效应器的阻断。这一结果为治疗小胶质炎性神经病变（如PD）提供了新的药物靶点。
Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa-opioid receptor (KOR). We show that microglial beta-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of beta-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for beta-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/beta-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD.