Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states

Kumar, Alok; Stoica, Bogdan A.; Sabirzhanov, Boris; Burns, Mark P.; Faden, Alan I.; Loane, David J.

doi:10.1016/j.neurobiolaging.2012.11.013

Cited by 219 publications

(242 citation statements)

References 71 publications

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“…Several conditions of priming exist. For instance, aged rodents demonstrate increased expression of mRNA and protein markers of inflammation following LPS challenge (Kumar et al, 2013;Norden and Godbout, 2013;Norden et al, 2015aNorden et al, , 2015b. In addition to aging, similar priming effects have been reported in microglia from patients with neuropsychiatric disorders including traumatic brain injury (Fenn et al, 2014) and neurodegeneration (Norden et al, 2015a).…”

Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 64%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 64%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

View full text Add to dashboard Cite

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“…For TBI-induced cortex and hippocampal neuronal cell loss, the optical fractionator method of stereology was used as previously described. 24 Briefly, every fourth 60 lm section between -1.22 and -2.54 mm from bregma was analyzed beginning from a random start point (i.e., the section where different hippocampal subregions were distinctly visible). A total of five sections were analyzed.…”

Section: Unbiased Stereological Assessment Of Neuronal Survivalmentioning

confidence: 99%

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Kumar

Álvarez‐Croda

Stoica

et al. 2016

Journal of Neurotrauma

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275

271

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Activated microglia and macrophages exert dual beneficial and detrimental roles after central nervous system injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion micro-environment following traumatic brain injury (TBI) using a moderate-level controlled cortical impact (CCI) model in mice. We performed a detailed phenotypic analysis of M1-and M2-like polarized microglia/macrophages, as well as nicotinamide adenine dinucleotide phosphate oxidase (NOX2) expression, through 7 days post-injury using real-time polymerase chain reaction (qPCR), flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1-and M2-like phenotypic markers early after TBI, but the transient up-regulation of the M2-like phenotype was replaced by a predominant M1-or mixed transitional (Mtran) phenotype that expressed high levels of NOX2 at 7 days post-injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study, we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 h post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time, resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity.

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“…Already 24 h after traumatic brain injury, microglia become activated and express NOX2 (98). In addition, it is possible that bloodderived inflammatory cells enter the CNS after injury.…”

Section: Traumatic Brain Injury and Chronic Traumatic Encephalopathymentioning

confidence: 99%

New Insights onNOXEnzymes in the Central Nervous System

Nayernia

Jaquet

Krause

2014

Antioxidants & Redox Signaling

248

231

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Significance: There is increasing evidence that the generation of reactive oxygen species (ROS) in the central nervous system (CNS) involves the NOX family of nicotinamide adenine dinucleotide phosphate oxidases. Controlled ROS generation appears necessary for optimal functioning of the CNS through fine-tuning of redoxsensitive signaling pathways, while overshooting ROS generation will lead to oxidative stress and CNS disease. Recent Advances: NOX enzymes are not only restricted to microglia (i.e. brain phagocytes) but also expressed in neurons, astrocytes, and the neurovascular system. NOX enzymes are involved in CNS development, neural stem cell biology, and the function of mature neurons. While NOX2 appears to be a major source of pathological oxidative stress in the CNS, other NOX isoforms might also be of importance, for example, NOX4 in stroke. Globally speaking, there is now convincing evidence for a role of NOX enzymes in various neurodegenerative diseases, cerebrovascular diseases, and psychosis-related disorders. Critical Issues: The relative importance of specific ROS sources (e.g., NOX enzymes vs. mitochondria; NOX2 vs. NOX4) in different pathological processes needs further investigation. The absence of specific inhibitors limits the possibility to investigate specific therapeutic strategies. The uncritical use of non-specific inhibitors (e.g., apocynin, diphenylene iodonium) and poorly validated antibodies may lead to misleading conclusions. Future Directions: Physiological and pathophysiological studies with cell-type-specific knock-out mice will be necessary to delineate the precise functions of NOX enzymes and their implications in pathomechanisms. The development of CNS-permeant, specific NOX inhibitors will be necessary to advance toward therapeutic applications. Antioxid. Redox Signal. 20, 2815Signal. 20, -2837

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Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states

Cited by 219 publications

References 71 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

New Insights onNOXEnzymes in the Central Nervous System

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