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

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…83 Similarly, in an in vitro study DRD2 receptors inhibited NLRP3 inflammasome activation in a β-arrestin2-dependent manner, whereas in MPTP-induced PD, DRD2 reduced the caspase-1 and IL-1β levels in the midbrain. 84 Thus, it clearly demonstrates a correlation between the level of DA and microglial NLRP3 inflammasome activation in PD.…”

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

“…In this study, we generated mice with the potential for DA neuron specific NLRP3 inflammasome hyperactivity and analyzed the animals throughout aging ( others who report suppression of NLRP3 inflammasome-driven inflammation dependent on the DRD1 dopamine receptor in bone marrow derived macrophages [67]. In a related report, astroglial DRD2 receptors are similarly implicated in suppression of NLRP3 inflammasome activity [68]. Critically, DA neurons express DRD2 autoreceptors that are involved in regulating the synthesis, release, and uptake of dopamine in presynaptic cells [69].…”

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

“…However, functional research on dopamine receptors has focused on neurons because dopamine is a well-known neurotransmitter. The function of astrocytic dopamine receptors was long overlooked until we recently reported that activation of the astrocytic dopamine D2 receptor (DRD2) can suppress neuroinflammation in PD 23,24 . Because GSH is mainly synthesized in astrocytes in the brain [25][26][27] and dopamine receptors on astrocytes are functional, we hypothesized that astrocytic dopamine receptors regulate GSH synthesis.…”