| First Author | Zhu J | Year | 2018 |
| Journal | Cell Death Differ | Volume | 25 |
| Issue | 11 | Pages | 2037-2049 |
| PubMed ID | 29786071 | Mgi Jnum | J:302819 |
| Mgi Id | MGI:6510102 | Doi | 10.1038/s41418-018-0127-2 |
| Citation | Zhu J, et al. (2018) Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of beta-arrestin2 and NLRP3. Cell Death Differ 25(11):2037-2049 |
| abstractText | Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1beta (IL-1beta) 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-1beta 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-1beta 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-1beta 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. |
