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Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase
- Source :
- Journal of Neuroscience, Vol. 28, No 46 (2008) pp. 12039-12051, Journal of Neuroscience, Journal of Neuroscience, 2008, 28 (46), pp.12039-51. ⟨10.1523/JNEUROSCI.3568-08.2008⟩, Journal of Neuroscience, Society for Neuroscience, 2008, 28 (46), pp.12039-51. ⟨10.1523/JNEUROSCI.3568-08.2008⟩
- Publication Year :
- 2008
-
Abstract
- Reactive oxygen species (ROS) modulate intracellular signaling but are also responsible for neuronal damage in pathological states. Microglia, the resident CNS macrophages, are prominent sources of ROS through expression of the phagocyte oxidase which catalytic subunit Nox2 generates superoxide ion (O2·−). Here we show that microglia also express Nox1 and other components of nonphagocyte NADPH oxidases, including p22phox, NOXO1, NOXA1, and Rac1/2. The subcellular distribution and functions of Nox1 were determined by blocking Nox activity with diphenylene iodonium or apocynin, and by silencing theNox1gene in microglia purified from wild-type (WT) or Nox2-KO mice. [Nox1-p22phox] dimers localized in intracellular compartments are recruited to phagosome membranes during microglial phagocytosis of zymosan, and Nox1 produces O2·−in zymosan-loaded phagosomes. In microglia activated with lipopolysaccharide (LPS), Nox1 produces O2·−, which enhances cell expression of inducible nitric oxide synthase and secretion of interleukin-1β. Comparisons of microglia purified from WT, Nox2-KO, or Nox1-KO mice indicate that both Nox1 and Nox2 are required to optimize microglial production of nitric oxide. By injecting LPS in the striatum of WT and Nox1-KO mice, we show that Nox1 also enhances microglial production of cytotoxic nitrite species and promotes loss of presynaptic proteins in striatal neurons. These results demonstrate the functional expression of Nox1 in resident CNS phagocytes, which can promote production of neurotoxic compounds during neuroinflammation. Our study also shows that Nox1- and Nox2-dependent oxidases play distinct roles in microglial activation and that Nox1 is a possible target for the treatment of neuroinflammatory states.
- Subjects :
- Lipopolysaccharides
rac1 GTP-Binding Protein
Male
MESH: Membrane Glycoproteins
MESH: rac GTP-Binding Proteins
ddc:616.07
MESH: Neuropeptides
MESH: Mice, Knockout
MESH: Corpus Striatum
chemistry.chemical_compound
Mice
0302 clinical medicine
Gliosis/enzymology/physiopathology
NADH, NADPH Oxidoreductases
MESH: Animals
MESH: Proteins
Gliosis
MESH: NADPH Oxidase
Mice, Knockout
0303 health sciences
NADPH oxidase
Membrane Glycoproteins
MESH: NADH, NADPH Oxidoreductases
MESH: Oxidative Stress
biology
Microglia
Superoxide
Nitrites/metabolism
General Neuroscience
MESH: Nitrites
NADPH Oxidase/genetics/metabolism
MESH: Reactive Oxygen Species
MESH: Gliosis
Articles
Cell biology
rac GTP-Binding Proteins
Nitric oxide synthase
MESH: Microglia
medicine.anatomical_structure
Biochemistry
NOX1
NADPH Oxidase 2
NADPH Oxidase 1
cardiovascular system
Encephalitis
[SDV.IMM]Life Sciences [q-bio]/Immunology
Female
Inflammation Mediators
Zymosan/metabolism
Rac GTP-Binding Proteins/genetics/metabolism
MESH: Zymosan
[SDV.IMM] Life Sciences [q-bio]/Immunology
Neurotoxins
MESH: Inflammation Mediators
NADH, NADPH Oxidoreductases/genetics/metabolism
Cytochrome b Group/genetics/metabolism
Corpus Striatum/drug effects/enzymology/physiopathology
Neurotoxins/pharmacology
Microglia/drug effects/enzymology
Nitric oxide
03 medical and health sciences
MESH: Mice, Inbred C57BL
Reactive Oxygen Species/metabolism
medicine
MESH: Cytochrome b Group
Animals
Oxidative Stress/drug effects/physiology
MESH: Mice
Neuroinflammation
Nitrites
030304 developmental biology
Adaptor Proteins, Signal Transducing
MESH: Neurotoxins
Encephalitis/enzymology/physiopathology
Neuropeptides/genetics/metabolism
Neuropeptides
Zymosan
NADPH Oxidases
Proteins
Proteins/genetics/metabolism
Membrane Glycoproteins/genetics
Cytochrome b Group
Lipopolysaccharides/pharmacology
Corpus Striatum
MESH: Male
Inflammation Mediators/pharmacology
Mice, Inbred C57BL
Oxidative Stress
chemistry
Apocynin
biology.protein
MESH: Encephalitis
MESH: Lipopolysaccharides
Reactive Oxygen Species
MESH: Female
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 02706474 and 15292401
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience, Vol. 28, No 46 (2008) pp. 12039-12051, Journal of Neuroscience, Journal of Neuroscience, 2008, 28 (46), pp.12039-51. ⟨10.1523/JNEUROSCI.3568-08.2008⟩, Journal of Neuroscience, Society for Neuroscience, 2008, 28 (46), pp.12039-51. ⟨10.1523/JNEUROSCI.3568-08.2008⟩
- Accession number :
- edsair.doi.dedup.....c4bd8b1d4b7b5941f05be0db0b6c250e