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Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase

Chéret, Cyril
Gervais, Annie
Lelli, Aurélia
Colin, Catherine
Amar, Lahouari
Ravassard, Philippe
Mallet, Jacques
Cumano, Ana
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Published in The journal of neuroscience. 2008, vol. 28, no. 46, p. 12039-12051
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 p22(phox), 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 the Nox1 gene in microglia purified from wild-type (WT) or Nox2-KO mice. [Nox1-p22(phox)] 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-1beta. 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.
Keywords AnimalsCorpus Striatum/drug effects/enzymology/physiopathologyCytochrome b Group/genetics/metabolismEncephalitis/enzymology/physiopathologyFemaleGliosis/enzymology/physiopathologyInflammation Mediators/pharmacologyLipopolysaccharides/pharmacologyMaleMembrane Glycoproteins/geneticsMiceMice, Inbred C57BLMice, KnockoutMicroglia/drug effects/enzymologyNADH, NADPH Oxidoreductases/genetics/metabolismNADPH Oxidase/genetics/metabolismNeuropeptides/genetics/metabolismNeurotoxins/pharmacologyNitrites/metabolismOxidative Stress/drug effects/physiologyProteins/genetics/metabolismReactive Oxygen Species/metabolismZymosan/metabolismRac GTP-Binding Proteins/genetics/metabolism
PMID: 19005069
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Other version: http://www.jneurosci.org/cgi/content/full/28/46/12039
Research groups Groupe Schaller Karl-Lothard (neurochirurgie) (851)
Radicaux libres et cellules souches embryonnaires (60)
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CHÉRET, Cyril et al. Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase. In: The Journal of neuroscience, 2008, vol. 28, n° 46, p. 12039-12051. doi: 10.1523/JNEUROSCI.3568-08.2008 https://archive-ouverte.unige.ch/unige:2184

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Deposited on : 2009-06-29

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