Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway

Hou, Liyan; Wang, Ke; Zhang, Cong; Sun, Fuqiang; Che, Yuning; Zhao, Xianxian; Zhang, Dan; Li, Huihua; Wang, Qingshan

doi:10.1016/j.redox.2017.09.017

Cited by 86 publications

(61 citation statements)

References 58 publications

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“…Furthermore, Yeh et al (2013) found that modulated Src−ERK1/2−NF-κB pathway could attenuate LPS−induced PGE 2 and NO production in BV−2 microglial cells. Besides, Hou et al (2017) demonstrated that Src-Erk-dependent pathway was involved in complement receptor 3-mediated NADPH oxidase activation and dopaminergic neurodegeneration. In addition, our previous study showed that inhibiting Src signaling pathway may have potential anti-neuroinflammatory effects (Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

et al. 2020

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Chronic neuroinflammation is of great importance in the pathogenesis of Parkinson's disease (PD). During the process of neuroinflammation, overactivated microglia release many proinflammatory factors, which eventually induce neurodegeneration. Inhibition of excessive microglial activation is regarded as a promising strategy for PD treatment. Src is a non-receptor tyrosine kinase that is closely related to tumors. Recently, some reports indicated that Src is a central mediator in multiple signaling pathways including neuroinflammation. The aim of our study was to demonstrate the role of Src in microglial regulation and neuroinflammation. The lipopolysaccharide (LPS)-stimulated BV2 microglia model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced PD model were applied in this study. The results showed that inhibition of Src could significantly relieve microgliosis and decrease levels of inflammatory factors. Besides, inhibition of Src function reduced the loss of dopaminergic neurons and improved the motor behavior of the MPTP-treated mice. Thus, this study not only verified the critical role of Src tyrosine kinase in neuroinflammation but also further proved that interfering neuroinflammation is beneficial for PD treatment. More importantly, this study shed a light on the hypothesis that Src tyrosine kinase might be a potential therapeutic target for PD and other neuroinflammation-related diseases.

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Section: Discussionmentioning

confidence: 99%

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

et al. 2020

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“…Gait measurement was performed by two individuals blind to the treatment and was analyzed as previously described 52 . The forelimbs and hindlimbs of each mouse were coated with red and blue nontoxic paints, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The cultures were maintained at 37 °C in the incubator with 5 % CO 2 and 95% air in minimum essential medium. The cultures were ready for experiments 7 days later, when the cultures became mature and stable of each cell component (~10% microglia, ~50% astrocytes, ~40% neurons and ~1% dopaminergic neurons) as described previously 52 . Microglia-depleted neuron-glia cultures were obtained by depleting microglia in neuron-glia cultures with 1.5 mM of LME 48 h after seeding (~45 % neurons and ~55 % astrocyte), as described previously 54 .…”

Section: Methodsmentioning

confidence: 99%

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Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

et al. 2018

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Microglia-mediated neuroinflammation is implicated in multiple neurodegenerative disorders, including Parkinson’s disease (PD). Hence, the modulatioein of sustained microglial activation may have therapeutic potential. This study is designed to test the neuroprotective efficacy of taurine, a major intracellular free β-amino acid in mammalian tissues, by using paraquat and maneb-induced PD model. Results showed that mice intoxicated with paraquat and maneb displayed progressive dopaminergic neurodegeneration and motor deficits, which was significantly ameliorated by taurine. Taurine also attenuated the aggregation of α-synuclein in paraquat and maneb-intoxicated mice. Mechanistically, taurine suppressed paraquat and maneb-induced microglial activation. Moreover, depletion of microglia abrogated the dopaminergic neuroprotective effects of taurine, revealing the role of microglial activation in taurine-afforded neuroprotection. Subsequently, we found that taurine suppressed paraquat and maneb-induced microglial M1 polarization and gene expression levels of proinflammatory factors. Furthermore, taurine was shown to be able to inhibit the activation of NADPH oxidase (NOX2) by interfering with membrane translocation of cytosolic subunit, p47phox and nuclear factor-kappa B (NF-κB) pathway, two key factors for the initiation and maintenance of M1 microglial inflammatory response. Altogether, our results showed that taurine exerted dopaminergic neuroprotection through inactivation of microglia-mediated neuroinflammation, providing a promising avenue and candidate for the potential therapy for patients suffering from PD.

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“…Activation of ERK by phosphorylation is a key step in regulation of microglial pro-inflammatory phenotype [33,34], and is known to play a role in microglial pro-inflammatory processes in a Parkinson's disease mouse model [35,36]. We hypothesized that this pathway might be involved in promotion of the anti-inflammatory phenotype by monomeric α-Syn.…”

Section: Monomeric α-Syn May Regulate Microglia Towards Anti-inflammamentioning

confidence: 99%

Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

Stewart

Sheng

et al. 2020

Preprint

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BACKGROUNDMicroglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. It is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e. mostly desirable functions of microglia in a physiological state. What maintains microglia at this physiological state is essentially unknown, despite significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease.METHODSIn this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ,IL-4 + IL-13, α-synuclein monomer and α-synuclein oligomer, examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. RESULTS: We described a novel physiological function of α-synuclein, in which it modulates microglia towards an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. CONCLUSIONS: These findings suggest a previously unrecognized function of α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

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Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway

Cited by 86 publications

References 58 publications

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization

Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

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