Abstract:According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson’s disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodeg… Show more
“…The NLRP3 inflammasome, an important component of inflammation, is a complex of multiple proteins, including NLRP3, ASC and caspase-1, which are expressed abundantly in microglia [ 17 , 45 ]. When stimulated, the NLRP3 complex leads to caspase-1 activation, promotes the maturation and secretion of the proinflammatory cytokines IL-1β and IL-18, and induces the shift of microglia into an anti-inflammatory state [ 46 ], while inhibition the NLRP3 inflammasome suppresses microglial polarization to a proinflammatory state [ 47 ].…”
Section: Discussionmentioning
confidence: 99%
“…Exome sequencing analysis of human NLRP3 gene variants revealed that multiple single-nucleotide polymorphisms were associated with a significantly reduced risk of PD development [ 15 ]. Moreover, inhibiting the NLRP3 inflammasome can reduce α-synuclein deposition, alleviate dopaminergic neuron damage and improve motor function [ 11 , 16 , 17 ].…”
Background
Circadian disturbance is a common nonmotor complaint in Parkinson’s disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis.
Methods
We first examined the diurnal Rev-erbα rhythms and diurnal changes in microglia-mediated inflammatory cytokines expression in the SN of MPTP-induced PD mice. Further, we used BV2 cell to investigate the impacts of Rev-erbα on NLRP3 inflammasome and microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail.
Results
BV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system.
Conclusions
These observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.
“…The NLRP3 inflammasome, an important component of inflammation, is a complex of multiple proteins, including NLRP3, ASC and caspase-1, which are expressed abundantly in microglia [ 17 , 45 ]. When stimulated, the NLRP3 complex leads to caspase-1 activation, promotes the maturation and secretion of the proinflammatory cytokines IL-1β and IL-18, and induces the shift of microglia into an anti-inflammatory state [ 46 ], while inhibition the NLRP3 inflammasome suppresses microglial polarization to a proinflammatory state [ 47 ].…”
Section: Discussionmentioning
confidence: 99%
“…Exome sequencing analysis of human NLRP3 gene variants revealed that multiple single-nucleotide polymorphisms were associated with a significantly reduced risk of PD development [ 15 ]. Moreover, inhibiting the NLRP3 inflammasome can reduce α-synuclein deposition, alleviate dopaminergic neuron damage and improve motor function [ 11 , 16 , 17 ].…”
Background
Circadian disturbance is a common nonmotor complaint in Parkinson’s disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis.
Methods
We first examined the diurnal Rev-erbα rhythms and diurnal changes in microglia-mediated inflammatory cytokines expression in the SN of MPTP-induced PD mice. Further, we used BV2 cell to investigate the impacts of Rev-erbα on NLRP3 inflammasome and microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail.
Results
BV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system.
Conclusions
These observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.
“…4 ). We demonstrated that the cytosolic release of mtDNA induced by K + efflux in macrophages activates NLRP3 inflammasome and raises the possibility that dysregulated mitochondria as a therapeutic target for NLRP3 inflammasome-regulated diseases [ 7 , [38] , [39] , [40] ]. Fig.…”
“…Studies have found that the expression level of MBLs protein in the cerebrospinal fluid of AD patients is significantly reduced ( Moller-Kristensen et al, 2006 ), and the expression level of the anti-inflammatory factor Fetuin-A in the plasma of patients with mild to moderate AD is also significantly reduced ( Smith et al, 2011 ). Inflammatory targets for Parkinson’s Disease (PD) disease currently include α-synuclein and vitamin D ( Gambino et al, 2019 ; Li et al, 2021 ), both of which are also significantly down-regulated in the peripheral blood of PD patients. In addition, some studies have found that the blood brain barrier (BBB) of patients with neurodegenerative diseases is damaged, and the exosomes secreted by abnormally activated microglia can enter the peripheral blood through the BBB, and the contents contained in the exosomes can be detected ( Guo et al, 2021 ).…”
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