Measurement and Characterization of Superoxide Generation in Microglial Cells: Evidence for an NADPH Oxidase-Dependent Pathway

Sankarapandi, Sornampillai; Zweíer, Jay L.; Mukherjee, Goutam; Quinn, Mark T.; Huso, David L.

doi:10.1006/abbi.1998.0658

Cited by 127 publications

(111 citation statements)

References 45 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…Unlike the regulation of iNOS, the principal regulation of NADPH oxidase is posttranslational and depends on assembly of several membrane-bound and cytosolic components to form an active enzyme complex. Although the kinetics and magnitude of superoxide generation appear to be different in microglia as compared with, for example, neutrophils, microglia appear to express all of the components of the oxidase and generate superoxide upon activation (25). Our results demonstrate that microglia are the primary cells expressing the oxidase, and LPS challenge did not increase gp91 phox expression but, instead, activated the enzyme.…”

Section: Discussionmentioning

confidence: 54%

“…Activation of the oxidase represents an essential mechanism of host defense against various pathogens. It has been recently demonstrated that microglia also possess a similar NADPH oxidase (25). Because microglia are thought to be derived from monocytes during early brain development, and because microglia have the full capacity to be induced and develop into macrophages in the CNS, we next asked whether NADPH oxidase was required for the cytotoxic effect of activated microglia.…”

Section: Activation Of the Superoxide-generating Nadph Oxidase In Micmentioning

confidence: 99%

See 1 more Smart Citation

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

Lǐ

Baud

Vartanian

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

334

255

View full text Add to dashboard Cite

Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (iNOS) after LPS challenge; microglia from iNOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxidegenerating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91 phox , failed to induce cell death. Our results reveal a role for NADPH oxidase in LPSinduced OL death and suggest that peroxynitrite produced by iNOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.inflammation ͉ lipopolysaccharide ͉ cerebral palsy ͉ reactive nitrogen species ͉ periventricular leukomalacia M icroglia are the resident macrophage-like cells of the CNS.They play a pivotal role in the innate immune response of CNS and are the first line of defense against microorganism invasion and injury (1). Localized activation of microglia, however, has also been implicated in the pathogenesis of a number of neurological diseases and disorders, including ischemia; AIDS-associated dementia (2); chronic neurodegenerative diseases (3), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and white matter disorders, such as multiple sclerosis (4) and periventricular leukomalacia (PVL) (5). Microglia are extremely responsive to environmental or immunological challenges and are the predominant cell type producing inflammation-mediated neurodegeneration. Upon activation, microglia release proinflammatory molecules, such as cytokines and chemokines, and mediators of cell injury, such as proteases and reactive oxygen species (ROS)͞reactive nitrogen species (6-8). Although necessary for normal functions, activation of microglia requires tight regulation to avoid bystander injury to other CNS cells. The identification of primary toxic factors, localization of their molecular sources, and the elucidation of signaling pathways associated with microglial overactivation are therefore of paramount importance to our understanding of cellular injury in the CNS.PVL is the lesion of cerebral white matter that underlies most cases of cerebral palsy developing in premature infants (9). It is characterized by focal necrotic lesions in the deep white matter and by diffuse injury to premyelinatin...

show abstract

Section: Discussionmentioning

confidence: 54%

Section: Activation Of the Superoxide-generating Nadph Oxidase In Micmentioning

confidence: 99%

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

Lǐ

Baud

Vartanian

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

334

255

View full text Add to dashboard Cite

show abstract

“…Nox2 is expressed in relatively high levels in microglia [156], the principal immune effector cell in the brain, where it participates in host defense and inflammatory responses in this organ [157]. Nox4 is expressed in neurons and capillaries of the brain, and is up-regulated during ischemia [158].…”

Section: Nox Enzymes In Brain and Nerve A Roles For Nox-derived Ros mentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

591

454

View full text Add to dashboard Cite

“…Microglia may lead to cellular damage in Alzheimer's disease not only through the generation of ROS products [195], but also through the production of cytokines and the demise of neighboring neurons and ECs [18,152]. Microglia promote the production of pro-inflammatory and cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, free radicals such as NO and superoxide [195], and fatty acid metabolites such as eicosanoids that can precipitate cell death [128].…”

Section: A Potential Detrimental Role For Microglia During Alzheimer'mentioning

confidence: 99%

“…Microglia promote the production of pro-inflammatory and cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, free radicals such as NO and superoxide [195], and fatty acid metabolites such as eicosanoids that can precipitate cell death [128]. TNF-α production by microglia may be linked to neurodegeneration by increasing the sensitivity of neurons to free radical exposure [53].…”

Section: A Potential Detrimental Role For Microglia During Alzheimer'mentioning

confidence: 99%

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Chong

Maiese

2005

Brain Research Reviews

135

121

View full text Add to dashboard Cite

More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of β-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3β, Bad, and Bcl-x L . Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

show abstract

Measurement and Characterization of Superoxide Generation in Microglial Cells: Evidence for an NADPH Oxidase-Dependent Pathway

Cited by 127 publications

References 45 publications

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Contact Info

Product

Resources

About