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Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of ?-arrestin2 and NLRP3.

ABSTRACT: Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1? (IL-1?) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. ?-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? 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? release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in ?-arrestin2 knockout and ?-arrestin2 small interfering RNA-injected mice, suggesting a critical role of ?-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1? expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that ?-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 ?-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.

SUBMITTER: Zhu J

PROVIDER: S-EPMC6219479 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3.

Zhu Jialei J Hu Zhaoli Z Han Xiaojuan X Wang Dongshuo D Jiang Qingling Q Ding Jianhua J Xiao Ming M Wang Cong C Lu Ming M Hu Gang G

Cell death and differentiation 20180521 11

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 ...[more]

PMID: 29786071

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Project description:The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. SIGNIFICANCE STATEMENT: The NLRP3 inflammasome plays central role in innate immune sensing and control of inflammation. Pharmacological inhibition of NLRP3 demonstrated promising efficacy in a range of diseases in animal models. Recent elucidation of the structure and inhibitor binding of NLRP3 generated new insights into its mode of action and inhibitor-NLRP3 interaction at molecular levels, providing new framework for developing small chemical inhibitors of NLRP3 with improved efficacy and specificity against chronic disease that has become major health concerns worldwide.

Dataset Information

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of ?-arrestin2 and NLRP3.

Publications

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3.

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