Abstract
Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson’s disease (PD). Among the numerous inflammatory cytokines, interleukin-1β (IL-1β) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. β-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-1β 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-1β release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in β-arrestin2 knockout and β-arrestin2 small interfering RNA-injected mice, suggesting a critical role of β-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1β expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that β-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 β-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.
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Acknowledgements
We would like to acknowledge Professor Gang Pei and Professor Jiawei Zhou for providing β-arrestin2−/− mice and Drd2 knockout (Drd2−/−) mice. We also thank Professor Guangyu Wu for critical reading of the manuscript. The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81630099, No. 81473196, No. 81773706, No. 81573403 and No. 81473195), the key project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 15KJA310002), and Natural Science Foundation of Jiangsu Province (BK20151559).
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Zhu, J., Hu, Z., Han, X. et al. Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3. Cell Death Differ 25, 2037–2049 (2018). https://doi.org/10.1038/s41418-018-0127-2
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DOI: https://doi.org/10.1038/s41418-018-0127-2
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