| Title: |
Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease |
| Authors: |
Pike A. F.; Longhena F.; Faustini G.; van Eik J. -M.; Gombert I.; Herrebout M. A. C.; Fayed M. M. H. E.; Sandre M.; Varanita T.; Teunissen C. E.; Hoozemans J. J. M.; Bellucci A.; Veerhuis R.; Bubacco L. |
| Contributors: |
Pike, A. F.; Longhena, F.; Faustini, G.; van Eik, J. -M.; Gombert, I.; Herrebout, M. A. C.; Fayed, M. M. H. E.; Sandre, M.; Varanita, T.; Teunissen, C. E.; Hoozemans, J. J. M.; Bellucci, A.; Veerhuis, R.; Bubacco, L. |
| Publisher Information: |
BioMed Central Ltd |
| Publication Year: |
2022 |
| Collection: |
Padua Research Archive (IRIS - Università degli Studi di Padova) |
| Subject Terms: |
Dopamine; Neuroinflammation; NLRP3 inflammasome; Parkinson’s disease; Potassium; Primary human microglia; α-Synuclein |
| Description: |
Background: 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. 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. Methods: Biochemical 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. Results: We 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/35172843; info:eu-repo/semantics/altIdentifier/wos/WOS:000756835500001; volume:19; issue:1; firstpage:50; journal:JOURNAL OF NEUROINFLAMMATION; https://hdl.handle.net/11577/3473608 |
| DOI: |
10.1186/s12974-022-02410-4 |
| Availability: |
https://hdl.handle.net/11577/3473608; https://doi.org/10.1186/s12974-022-02410-4 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.32417CD7 |
| Database: |
BASE |