Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson’s disease

Qin, Yue; Qiu, Jingru; Wang, Ping; Liu, Jia; Zhao, Yong; Jiang, Fan; Lou, Haiyan

doi:10.1016/j.bbi.2020.10.010

Cited by 126 publications

(82 citation statements)

References 29 publications

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“…Besides cell activation, PD-associated genes also disrupt other microglial processes including mitochondrial respiration and autophagy ( 99 ). Since autophagy is involved in regulating microglia inflammatory status ( 100 , 101 ), its disruption has been reported to play a critical role in inflammation ( 102 ) and may also affect some of the key functions of microglia including phagocytosis ( 101 ). Furthermore, autophagy failure has been shown to promote intercellular propagation of α-syn ( 103 ) which in turn drives microglial activation and neuroinflammation.…”

Section: Microglia and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.

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Section: Microglia and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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“…Emerging evidence has suggested that NLRP3 inflammasome activation, which is involved in microglial polarization, requires NF-κB-mediated NLRP3 activation. [50][51][52][53] In our previous study, we demonstrated that CYLD could negatively regulate the NF-κB signaling pathway. 27 A recent report showed that CYLD deficiency in macrophages profoundly promoted IL-1β secretion, active caspase-1 generation, apoptosis-associated speck-like protein containing speck (ASC) formation, and pyroptotic cell death in response to canonical activation of the NLRP3 inflammasome in a peritonitis mouse model.…”

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confidence: 98%

Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion

Lin¹,

Zhan²,

Jiang³

et al. 2021

JIR

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Background: Activated microglia are polarized into the M1 or M2 phenotype. We previously reported that electroacupuncture (EA) effectively prevented nuclear factor-κB (NF-κB) nuclear translocation and improved neuronal C-X-C motif 3 chemokine ligand 1 (CX3CL1) expression, repressing microglial activation by upregulating neuronal cylindromatosis (CYLD) expression in the periischemic cortex. However, the potential mechanisms are unclear. Therefore, we explored whether EA improved CYLD protein expression to regulate microglial polarization-mediated neuroinflammation and the potential mechanisms in an ischemic stroke model. Methods: A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats. The rats were treated with EA at the Baihui, Hegu and Taichong acupoints once daily beginning 2 h after focal cerebral ischemia. CYLD gene interference was used to investigate the role of CYLD in microglial polarization. We used neurobehavioral evaluations and TTC staining to examine the neuroprotective effect of EA via CYLD upregulation. Immunofluorescence and RT-qPCR were used to measure NLRP3 activation, M1/M2 microglial activation, pro-/anti-inflammatory gene mRNA expression and crosstalk (CX3CL1/CX3CR1 axis) between neurons and microglia. Western blotting was used to assess the underlying molecular mechanism. Results: CYLD inhibited M1 microglial activation and improved M2 microglial activation after 72 h of reperfusion. CYLD overexpression decreased the NLRP3 mRNA level. CYLD suppressed microglial overactivation by inhibiting NLRP3 activation. CYLD gene silencing partially weakened EA improvement of neurological function deficits and reduction of infarct volumes after 72 h reperfusion. In addition, EA inhibited M1-like phenotypic microglial activation and promoted M2-like phenotypic microglia through upregulating CYLD expression. Finally, EA-mediated modulation of the CX3CL1/CX3CR1 axis and NLRP3 inflammasome was reversed by CYLD gene silencing in the periischemic cortex. Conclusion: EA-induced upregulation of neuronal CYLD expression plays anti-inflammatory and neuroprotective roles and regulates the interaction between neurons and microglia, thereby suppressing M1 and improving M2 microglial activation in the periischemic cortex.

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“…Increasing evidence demonstrates that aberrant regulation of autophagy contributes to the aggregation of α-Syn and α-Syn-induced neurodegeneration in PD (Ebrahimi-Fakhari et al, 2012;Poehler et al, 2014;Xilouri et al, 2016;Hou et al, 2020;Senkevich and Gan-Or, 2020). First, several studies found that alteration of autophagy-lysosome pathway activity, including both CMA and macroautophagy, existed in brains of postmortem PD patients and experimental models of PD (Alvarez-Erviti et al, 2010;Cerri and Blandini, 2019;Lamonaca and Volta, 2020;Qin et al, 2020;Wan et al, 2020), revealing the direct correlation between autophagy and pathological process of PD. Second, abnormally aggregated α-Syn inclusions are mainly degraded by autophagy (Webb et al, 2003) and defects or deficiency of autophagy can lead to accumulation of intracellular misfolded amyloid α-Syn aggregates, thus causally linking autophagy to PD pathological process (Xilouri et al, 2016;Guo et al, 2020).…”

Section: Caffeine May Modulate Pd Pathology By Regulating Autophagy Amentioning

confidence: 99%

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

2020

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine’s action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for “personalized medicine” in PD.

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Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson’s disease

Cited by 126 publications

References 29 publications

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

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