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Cited by 431Inflammasome and immune disordersParkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration

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Lee, Eunju, Hwang, Inhwa, Park, Sangjun, Hong, Sujeong, Hwang, Boreum, Cho, Yoeseph, Son, Junghyun, Yu, Je-Wook·2019·Cell Death & Differentiation
DOI 10.1038/s41418-018-0124-5PMC PMC6329843
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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the reduction of dopamine levels in the striatum. Although details of the molecular mechanisms underlying dopaminergic neuronal death in PD remain unclear, neuroinflammation is also considered a potent mediator in the pathogenesis and progression of PD. In the present study, we present evidences that microglial NLRP3 inflammasome activation is critical for dopaminergic neuronal loss and the subsequent motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Specifically, NLRP3 deficiency significantly reduces motor dysfunctions and dopaminergic neurodegeneration of MPTP-treated mice. Furthermore, NLRP3 deficiency abolishes MPTP-induced microglial recruitment, interleukin-1β production and caspase-1 activation in the SN of mouse brain. In primary microglia and mixed glial cell cultures, MPTP/ATP treatment promotes the robust assembly and activation of the NLRP3 inflammasome via producing mitochondrial reactive oxygen species. Consistently, 1-methyl-4-phenyl-pyridinium (MPP + ) induces NLRP3 inflammasome activation in the presence of ATP or nigericin treatment in mouse bone-marrow-derived macrophages. These findings reveal a novel priming role of neurotoxin MPTP or MPP + for NLRP3 activation. Subsequently, NLRP3 inflammasome-active microglia induces profound neuronal death in a microglia-neuron co-culture model. Furthermore, Cx3Cr1 CreER -based microglia-specific expression of an active NLRP3 mutant greatly exacerbates motor deficits and dopaminergic neuronal loss of MPTP-treated mice. Taken together, our results indicate that microglial NLRP3 inflammasome activation plays a pivotal role in the MPTP-induced neurodegeneration in PD.

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  • NLRP3 knockdown or knockout reduced neuroinflammation and neurodegeneration in an MPTP-induced PD mouse model.

    “NLRP3 knockdown or knockout was also found to reduce neuroinflammation and neurodegeneration in an MPTP-induced PD mouse model.360,361”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [361]

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Cited by

Sorted by citations

Authors
Lee, E., Hwang, I., Park, S., Hong, S., Hwang, B., Cho, Y., Son, J., & Yu, J.-W.
Affiliations
  • Yonsei University (KR)
  • Korea Institute of Science and Technology (KR)
Corresponding author
Yu, Je-Wook
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2018-05-21
Volume
26
Issue
2
Pages
213-228
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/s41418-018-0124-5
PMC
PMC6329843
OpenAlex
W2804970493
Cited by
431
References
14
Citations by year
2026: 40 · 2025: 58 · 2024: 67 · 2023: 72 · 2022: 64 · 2021: 64 · 2020: 39 · 2019: 22 · 2018: 5
FWCI
11.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
  • National Research Foundation
  • National Research Foundation of Korea (2015M3A9B6073856, 2014R1A4A1008625, 2015M3A9B6073856, 2017R1A2B2007467, 2014R1A4A 1008625)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Parkinson's disease, NLRP3 inflammasome, microglia, dopaminergic neuron loss, MPTP, MPP+, neuroinflammation, IL-1β, caspase-1, reactive oxygen species, mitochondrial dysfunction, microglia-neuron co-culture, motor impairment, substantia nigra
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Behavior, Animal, Disease Models, Animal, Dopamine, Macrophages, Mice, Inbred C57BL, Neurotoxins, Parkinson Disease, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Cell Death, Microglia, Mice, Knockout, Mice, Gene Knockout Techniques, Inflammasomes, Dopaminergic Neurons

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