Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration

Chen, Shih‐Heng; Oyarzabal, Esteban A.; Hong, Jau–Shyong

doi:10.1016/j.coph.2015.10.001

Cited by 64 publications

(48 citation statements)

References 58 publications

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“…Loss of dopaminergic neurons in the substantia nigra is a main character in PD patients and PD animal models (Pringsheim et al 2014), which is associated with neuroinflammation in the area (Block et al 2007; Chen et al 2016). A single injection of LPS produced chronic neuroinflammation in mice (Qin et al 2007, 2013), whether injection of LPS could also produce neuroinflammation in rats is not known.…”

Section: Resultsmentioning

confidence: 99%

“…Neuroinflammation is a self-defense reaction to combat pathogen infection and typically transient and help maintain brain homeostasis. However, neuroinflammation might continue unresolved becoming persistent in pathological conditions (Block et al 2007; Chen et al 2016). For example, a single intraperitoneal injection of bacterial lipopolysaccharide (LPS) elicited a low-grade, long-lasting neuroinflammation leading to dopaminergic neuron loss and PD pathology several months later in mice (Qin et al 2007, 2013; Gao et al 2003, 2008)…”

Section: Introductionmentioning

confidence: 99%

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Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

Song

Wang

et al. 2018

Neurotox Res

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A single injection of LPS produced low-grade neuroinflammation leading to Parkinson’s disease (PD) in mice several months later. Whether such a phenomenon occurs in rats and whether such low-grade neuroinflammation would aggravate rotenone (ROT) neurotoxicity and disrupts circadian clock gene/protein expressions were examined in this study. Male rats were given two injections of LPS (2.5–7.5 mg/kg), and neuroinflammation and dopamine neuron loss were evident 3 months later. Seven months after a single LPS (5 mg/kg) injection, rats received low doses of ROT (0.5 mg/kg, sc, 5 times/week for 4 weeks) to examine low-grade neuroinflammation on ROT toxicity. LPS plus ROT produced more pronounced non-motor and motor dysfunctions than LPS or ROT alone in behavioral tests, and decreased mitochondrial complex 1 activity, together with aggravated neuroinflammation and neuron loss. The expressions of clock core genes brain and muscle Arnt-like protein-1 (Bmal1), locomotor output cycles kaput (Clock), and neuronal PAS domain protein-2 (Npas2) were decreased in LPS, ROT and LPS plus ROT groups. The expressions of circadian feedback genes Periods (Per1 and Per2) were also decreased, but Cryptochromes (Cry1 and Cry2) were unaltered. The circadian clock target genes nuclear receptor Rev-Erbα (Nr1d1), and D-box-binding protein (Dbp) expressions were also decreased. Consistent with the transcript levels, circadian clock protein BMAL1, CLOCK, NR1D1 and DBP were also decreased. Thus, LPS-induced chronic low-grade neuroinflammation potentiated ROT neurotoxicity and disrupted circadian clock gene/protein expression, suggesting a role of disrupted circadian in PD development and progression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

Song

Wang

et al. 2018

Neurotox Res

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“…In this series of studies, we assessed the consequence of lacking either NLRP3 or IL-1R1 on the induction of acute factors such as TNFα, and delayed factors including MHC-II, NOX2 (gp91), and Mac1. These delayed factors are necessary for sustained reactive microgliosis and long-lasting neuroinflammation [11,21,[58][59][60][61][62][63][64][65][66][67].…”

Section: Genetic/pharmacological Inhibition Of Nlrp3 or Il-1r1 Represmentioning

confidence: 99%

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Zhao

Wang

Zhou

et al. 2020

J Neuroinflammation

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Background: Sepsis-associated acute brain inflammation, if unresolved, may cause chronic neuroinflammation and resultant neurodegenerative diseases. However, little is known how the transition from acute to chronic neuroinflammation, which is critical for the following progressive neurodegeneration, occurs in sepsis. The goal of this study was to investigate potential immune factors regulating the transition process using a widely used endotoxemia LPS mouse model. This model shows distinct acute and chronic phases of neuroinflammation and recapitulates many cardinal features of Parkinson's disease, thus, providing a unique opportunity for studying phase transition of neuroinflammation.Methods: C57BL/6 J, NLRP3 −/− , and IL-1R1 −/− mice were employed. Mild and severe endotoxemia were produced by LPS ip injection at 1 or 5 mg/kg. Neuroinflammation in vitro and in vivo was assessed with proinflammatory cytokine expression by qPCR or ELISA and microglial activation by immunohistochemical analysis. Neurodegeneration was measured by manual and stereological counts of nigral dopaminergic neurons and immunohistochemical analysis of protein nitrosylation and α-synuclein phosphorylation. Results: LPS-elicited initial increases in mouse brain mRNA levels of TNFα, IL-6, IL-1β, and MCP-1, and nigral microglial activation were not dose-related. By contrast, the delayed increase in brain mature IL-1β levels was dependent on LPS doses and protracted nigral microglial activation was only observed in high dose of LPS-treated mice. LPS-elicited increase in brain mature IL-1β but not IL-1α level was NLRP3-dependent. After high dose LPS treatment, deficiency of NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished chronic neuroinflammation. Genetic or pharmacological inhibition of the NLRP3-IL-1β axis repressed LPS-stimulated upregulation of chronic neuroinflammatory mediators including MHC-II, NOX2, and Mac1, and protected dopaminergic neurons. Ten months after LPS-elicited severe endotoxemia, nigral persisted microglial activation, elevated nitrosylated proteins and phosphorylated α-synuclein, and significant neuronal degeneration developed in wild-type mice but not in NLRP3 −/− or IL-1R1 −/− mice.

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“…Activated NADPH oxidases (NOXs) – a family including NOX1, NOX2, NOX3, NOX4, NOX5, dual oxidase 1 (DUOX1) and DUOX2 – are a primary source of ROS via transporting electrons from intracellular NADPH, across biological membrane, and then to extracellular oxygen, generating superoxide [102, 103]. Among these seven isozymes, NOX2 is the prototype form and plays central roles in neuroinflammation, neurodegeneration and associated functional deficits in neurological conditions such as spinal cord injury [104], Parkinson’s disease [105, 106], Alzheimer’s disease (AD) [107], amyotrophic lateral sclerosis [108], multiple sclerosis [109], and epilepsy [110]. …”

Section: Nox2 Inhibitorsmentioning

confidence: 99%

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Dey

Jiang

et al. 2016

Trends in Pharmacological Sciences

170

132

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As a crucial component of brain innate immunity, neuroinflammation initially contributes to neuronal tissue repair and maintenance. However, chronic inflammatory processes within the brain and associated blood-brain barrier impairment often cause neurotoxicity and hyperexcitability. Mounting evidence points to a mutual facilitation between inflammation and epilepsy, suggesting that blocking the undesired inflammatory signaling within the brain might provide novel strategies to treat seizures and epilepsy. Neuroinflammation is primarily characterized by the upregulation of proinflammatory mediators in epileptogenic foci, among which, cyclooxygenase-2/prostaglandin E2, interleukin-1β, transforming growth factor-β, toll-like receptor 4, high-mobility group box 1, and tumor necrosis factor-α have been extensively studied. Small molecules that specifically target these key proinflammatory perpetrators have been evaluated for antiepileptic and antiepileptogenic effects in animal models. These important preclinical studies provide new insights into the regulation of inflammation in epileptic brains and guide drug discovery efforts aimed at developing novel anti-inflammatory therapies for seizures and epilepsy.

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Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration

Cited by 64 publications

References 58 publications

Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

A novel role of NLRP3-generated IL-1β in the acute-chronic transition of peripheral lipopolysaccharide-elicited neuroinflammation: implications for sepsis-associated neurodegeneration

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

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