Abstract
BackgroundParkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1β (IL-1β), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models. Fibrillar α-syn activates this inflammasome in mouse and human macrophages, and we have shown previously that the same holds true for primary human microglia. Dopamine blocks microglial NLRP3 inflammasome activation in the MPTP model, but its effects in this framework, highly relevant to PD, remain unexplored in primary human microglia and in other in vivo parkinsonism models.MethodsBiochemical techniques including quantification of IL-1β secretion and confocal microscopy were employed to gain insight into dopamine signaling-mediated inhibition of the NLRP3 inflammasome mechanism in primary human microglia and the SYN120 transgenic mouse model. Dopamine and related metabolites were applied to human microglia together with various inflammasome activating stimuli. The involvement of the receptors through which these catecholamines were predicted to act were assessed with agonists in both species.ResultsWe show in primary human microglia that dopamine, l-DOPA, and high extracellular K+, but not norepinephrine and epinephrine, block canonical, non-canonical, and α-syn-mediated NLRP3 inflammasome-driven IL-1β secretion. This suggests that dopamine acts as an inflammasome inhibitor in human microglia. Accordingly, we provide evidence that dopamine exerts its inhibitory effect through dopamine receptor D1 and D2 (DRD1 and DRD2) signaling. We also show that aged mice transgenic for human C-terminally truncated (1–120) α-syn (SYN120 tg mice) display increased NLRP3 inflammasome activation in comparison to WT mice that is diminished upon DRD1 agonism.ConclusionsDopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K+. We suggest that dopamine serves as an endogenous repressor of the K+ efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology.
Highlights
Parkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation
We demonstrated previously the ability of α-synuclein to activate the NLRP3 inflammasome in primary human microglia leading to IL-1β processing in a manner that was dependent on NLRP3 oligomerization but unaffected by caspase-1 inhibition, suggesting the potential for noncanonical inflammasome activation involvement in this process in human microglia as opposed to mouse models [29]
DA acts on the DA receptors of surrounding cells to exert its effects, so the present study explored with the help of agonists the participation of DA receptors in the NLRP3 inflammasome (See figure on page.) Fig. 5 Strong microglia activation and increased microglial inflammasome activation evident in syn of 120 aa (SYN120) tg mice as compared to WT mice is counteracted by DRD1 agonism. a Representative confocal images showing Iba-1 and NLRP3 immunopositivity in striatum of 12-month-old WT mice, SYN120 tg mice, SYN120 tg mice treated for 1 month with saline vehicle (SYN120 tg vehicle), and SYN120 tg mice treated for 1 month with 10 mg/kg/day SKF38393 (SYN120 tg SKF38393)
Summary
Parkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Parkinson’s disease (PD) pathology manifests with several characteristic features These include progressive neuronal degeneration that is prominent in the nigrostriatal dopaminergic system and results in the loss of basal ganglia dopamine (DA) inputs to elicit the onset of motor symptoms [1,2,3,4]. A second identifying aspect of PD pathology is the presence of intraneuronal and intraneuritic protein deposits known as Lewy bodies and Lewy neurites, respectively. These structures are enriched in α-synuclein (α-syn) fibrils [5,6,7,8]. One pathological mechanism with established links to all of these fundamental facets of PD is the NLRP3 inflammasome [12]
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