Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3
Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3
复制标题
多巴胺 D2 受体通过增强 β-arrestin2 和 NLRP3 的相互作用来限制星形胶质细胞 NLRP3 炎性体激活
DOI：
10.1038/s41418-018-0127-2
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发表时间：
2018-11-01
影响因子：
12.4
通讯作者：
Hu, Gang
中科院分区：
文献类型：
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作者：
Zhu, Jialei;Hu, Zhaoli;Hu, Gang
星形胶质细胞参与神经退行性疾病的神经炎症，如帕金森病（PD）。在众多的炎性细胞因子中，由星形胶质细胞Nod样受体蛋白（NLRP）炎性小体产生的白细胞介素-1 β（IL-1 β）在PD的发病机制中至关重要。β-arrestin 2介导的多巴胺D2受体（Drd 2）信号转导被认为是潜在的抗炎靶点。我们先前的研究表明星形胶质细胞Drd 2抑制中枢神经系统的神经炎症。然而，Drd 2在星形胶质细胞NLRP 3炎性小体活化和随后的IL-1 β产生中的作用仍不清楚。在本研究中，我们使用1-甲基-4-苯基-1，2，3，6-四氢吡啶诱导的PD小鼠模型来研究Drd 2是否可以抑制星形胶质细胞NLRP 3炎性小体激活。我们发现Drd 2激动剂抑制NLRP 3炎性小体活化，这通过野生型小鼠中脑中半胱天冬酶-1表达减少和IL-1 β释放减少来证明。在β-arrestin 2敲除和β-arrestin 2小干扰RNA注射小鼠中，Drd 2的抗炎体作用被消除，这表明β-arrestin 2在Drd 2调节的NLRP 3炎性体激活中起关键作用。我们还发现，Drd 2激动剂抑制了在原代培养的小鼠星形胶质细胞中响应于脂多糖加三磷酸腺苷诱导的NLRP 3炎性体激活的caspase-1和IL-1 β表达的上调。此外，我们证明了β-arrestin 2介导了Drd 2通过与NLRP 3相互作用并干扰炎性小体组装来抑制NLRP 3炎性小体激活的作用。总的来说，我们的研究表明星形胶质细胞Drd 2通过β-arrestin 2依赖性机制抑制NLRP 3炎性小体激活，并为PD的治疗提供了新的策略。
Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1 beta (IL-1 beta) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. beta-arrestin2-mediated dopamine D2 receptor (Drd2) signal transduction has been regarded as a potential anti-inflammatory target. Our previous study revealed that astrocytic Drd2 suppresses neuroinflammation in the central nervous system. However, the role of Drd2 in astrocytic NLRP3 inflammasome activation and subsequent IL-1 beta production remains unclear. In the present study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model to investigate whether Drd2 could suppress astrocytic NLRP3 inflammasome activation. We showed that Drd2 agonist inhibited NLRP3 inflammasome activation, evidenced by decreased caspase-1 expression and reduced IL-1 beta release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in beta-arrestin2 knockout and beta-arrestin2 small interfering RNA-injected mice, suggesting a critical role of beta-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1 beta expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that beta-arrestin2 mediated the inhibitory effect of Drd2 on NLRP3 inflammasome activation via interacting with NLRP3 and interfering the inflammasome assembly. Collectively, our study illustrates that astrocytic Drd2 inhibits NLRP3 inflammasome activation through a beta-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.