NADPH oxidase isoform expression is temporally regulated and may contribute to microglial/macrophage polarization after spinal cord injury

Bermudez, Sara; Khayrullina, Guzal; Zhao, Yujia; Byrnes, Kimberly R.

doi:10.1016/j.mcn.2016.10.001

Cited by 35 publications

(28 citation statements)

References 46 publications

(67 reference statements)

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“…Microglial activation, especially proinflammatory activation, produces not only proinflammatory cytokines but also ROS, resulting in oxidative stress in microenvironment [25,37]. In agreement with inhibition of microglial proinflammatory activation, glybenclamide treatment decreased the production of ROS in the brainstem of P + M-injected mice (Kruskal Wallis H test: H(2) = 7.538, p = 0.023; Fig.…”

Section: Glybenclamide Mitigates P + M-induced Oxidative Stress In Micesupporting

confidence: 65%

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Hou

Qiu

et al. 2020

J Neuroinflammation

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Background: The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson's disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. Methods: LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies. Results: Paraquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b −/− mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1β production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice.

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Section: Glybenclamide Mitigates P + M-induced Oxidative Stress In Micesupporting

confidence: 65%

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Hou

Qiu

et al. 2020

J Neuroinflammation

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“…Microglial cells are the resident tissue macrophages in the CNS and are on constant surveillance for perturbations resulting from injury. 28 However, different microglial activation profiles have been found in varied studies. 8 , 11 , 22 The results of glial cell quantification in the contusion rat SCI model showed a significant increase in glial cell density percentage at day 2 as compared to other days, and the highest increase in ED-1 immunoreactive cells was observed at day 2 (23.15%) post-injury.…”

Section: Discussionmentioning

confidence: 99%

The microglial activation profile and associated factors after experimental spinal cord injury in rats

Zhou¹,

Li²,

Zhu³

et al. 2018

NDT

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BackgroundSpinal cord injury (SCI) has imposed a great impact on the quality of life of patients due to its relatively young age of onset. The pathophysiology of SCI has been proven to be complicated. Microglia plays an important role in neuroinflammation and second injuries after SCI. Different environment and other factors may determine the microglial activation profile and what role they play. However, neither accurate time-course profiles of microglial activation nor influence factors have been demonstrated in varied SCI models.MethodsA rat compressive SCI model was used. Microglial activation profile and contents of inflammatory factors including IL-1β, IL-6 and TNF-α were detected. Myelination status as well as levels of iron and glutamate concentration, adenosine triphosphate (ATP) and potassium are also assessed.ResultsOur results showed that the activated microglia participating in immune-mediated responses peaked at day 7 post SCI and gradually decreased during the following 3 weeks. Contrarily, myelination and oligodendroglia showed an opposite trend, indicating that microglia may be a key factor partly through inflammatory reaction. Iron and glutamate concentration were found to be the highest at day 7 after SCI while both ATP and potassium reached a low valley at the same time.ConclusionThese findings showed a microglial activation profile and the alterations of associated factors after experiment SCI model. Moreover, our data suggest that high iron and glutamate concentration may be released by damaged oligodendroglia and contribute to the activation of microglial after SCI.

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“…Immunofluorescence has indicated NOX2 is the most responsive isotype to mechanical brain and spinal cord injury, with elevated expression persisting beyond 28-days post-injury in line with its robust expression [ 64 , 87 ]. Genetic deletion or pharmacological inhibition of NOX2 in a mouse model of traumatic brain injury (TBI) demonstrates attenuation of pro-inflammatory microglial phenotype, indicated by reduced expression of cytokines, including IL1β, IL6 and TNFα, 1-day post-injury [ 88 ].…”

Section: Microglial Nox Is Activated In Inflammation and Neurodegementioning

confidence: 99%

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

2020

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Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.

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NADPH oxidase isoform expression is temporally regulated and may contribute to microglial/macrophage polarization after spinal cord injury

Cited by 35 publications

References 46 publications

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

The microglial activation profile and associated factors after experimental spinal cord injury in rats

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

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