Activated Microglia Initiate Motor Neuron Injury by a Nitric Oxide and Glutamate-Mediated Mechanism

Zhao, Weihua; Xie, Wenjie; Le, Weidong; Beers, David R.; He, Yi; Henkel, Jenny S.; Simpson, Ericka; Yen, Albert; Xiao, Qin; Appel, Stanley H.

doi:10.1093/jnen/63.9.964

Cited by 161 publications

(181 citation statements)

References 60 publications

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“…Once S. suis arrives in the CNS, it encounters microglia (as well as meningeal and perivascular macrophages), major brain-resident innate immune effector cells. In fact, microglia play an ambiguous role, since they may protect neurons by preventing the entry of pathogens into the brain, but they can also be toxic to surrounding neurons by releasing NO, glutamate, and proinflammatory cytokines (10,31,72). In addition, activated microglia have been implicated in neurodegeneration resulting from bacterial meningitis (47).…”

Section: Discussionmentioning

confidence: 99%

In VitroCharacterization of the Microglial Inflammatory Response toStreptococcus suis, an Important Emerging Zoonotic Agent of Meningitis

et al. 2010

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Streptococcus suis is an important swine and human pathogen responsible for septicemia and meningitis. In vivo research in mice suggested that in the brain, microglia might be involved in activating the inflammatory response against S. suis. The aim of this study was to better understand the interactions between S. suis and microglia. Murine microglial cells were infected with a virulent wild-type strain of S. suis. Two isogenic mutants deficient at either capsular polysaccharide (CPS) or hemolysin production were also included. CPS contributed to S. suis resistance to phagocytosis and regulated the inflammatory response by hiding proinflammatory components from the bacterial cell wall, while the absence of hemolysin, a potential cytotoxic factor, did not have a major impact on S. suis interactions with microglia. Wild-type S. suis induced enhanced expression of Toll-like receptor 2 by microglial cells, as well as phophotyrosine, protein kinase C, and different mitogen-activated protein kinase signaling events. However, cells infected with the CPS-deficient mutant showed overall stronger and more sustained phosphorylation profiles. CPS also modulated inducible nitric oxide synthase expression and further nitric oxide production from S. suis-infected microglia. Finally, S. suis-induced NF-B translocation was faster for cells stimulated with the CPS-deficient mutant, suggesting that bacterial cell wall components are potent inducers of NF-B. These results contribute to increase the knowledge of mechanisms underlying S. suis inflammation in the brain and will be useful in designing more efficient anti-inflammatory strategies for meningitis.

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Section: Discussionmentioning

confidence: 99%

In VitroCharacterization of the Microglial Inflammatory Response toStreptococcus suis, an Important Emerging Zoonotic Agent of Meningitis

et al. 2010

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“…LPS-activated WT microglia are cytotoxic to cocultured primary motor neurons owing to production of ROS (73). LPS-stimulated microglial cells carrying mutSOD1 are at baseline more activated than WT microglia, produce more superoxide, NO, and TNF-α, and are more injurious to primary cultured motor neurons (74,75).…”

Section: Microglia In Als: Lessons From Sod1mentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

139

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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“…52 This release can produce neuronal death in culture and in ex vivo slice preparations. 52,53 Glutamate release from microglia might thus contribute to ischemic brain injury, 54 but the effect of glutamate release from microglia is likely to be small relative to the effects of neuronal glutamate release and failure of astrocyte glutamate reuptake that occur during brain ischemia. Nonetheless, glutamate release from chronically activated microglia in the postischemic period could contribute to delayed neuronal death at infarct margins or after transient ischemia.…”

Section: Glutamatementioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Activated Microglia Initiate Motor Neuron Injury by a Nitric Oxide and Glutamate-Mediated Mechanism

Cited by 161 publications

References 60 publications

In VitroCharacterization of the Microglial Inflammatory Response toStreptococcus suis, an Important Emerging Zoonotic Agent of Meningitis

In VitroCharacterization of the Microglial Inflammatory Response toStreptococcus suis, an Important Emerging Zoonotic Agent of Meningitis

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Microglial Activation in Stroke: Therapeutic Targets

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