 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, November 12, 2008, 28(46):12039-12051; doi:10.1523/JNEUROSCI.3568-08.2008
Previous Article | Next Article
Neurobiology of Disease
Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase
Cyril Chéret,1,2 Annie Gervais,1,2 Aurélia Lelli,1,2 Catherine Colin,1,2 Lahouari Amar,2,3 Philippe Ravassard,2,3 Jacques Mallet,2,3 Ana Cumano,4 Karl-Heinz Krause,5 andMichel Mallat1,2 1Inserm, Unité Mixte de Recherche (UMR) 711, Institut Fédératif de Recherche 70, 75013 Paris, France, 2Université Pierre et Marie Curie Paris 06, 75005 Paris, France, 3Centre National de la Recherche Scientifique, UMR 7091, 75013 Paris, France, 4Inserm, U668, Institut Pasteur, 75724 Paris Cedex 15, France, and 5Biology of Ageing Laboratories, University of Geneva, 1211 Geneva, Switzerland
Correspondence should be addressed to Michel Mallat, Biologie des Interactions Neurones/Glie, Inserm, Unité Mixte de Recherche 711, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. Email: michel.mallat{at}upmc.fr
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 the Nox1 gene 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.
Key words: microglia; NADPH oxidase; Nox; nitric oxide; interleukin-1; LPS; neuroinflammation
Received July 29, 2008; revised Sept. 30, 2008; accepted Oct. 2, 2008.
Correspondence should be addressed to Michel Mallat, Biologie des Interactions Neurones/Glie, Inserm, Unité Mixte de Recherche 711, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. Email: michel.mallat{at}upmc.fr
This article has been cited by other articles:
D. J. Loane, B. A. Stoica, A. Pajoohesh-Ganji, K. R. Byrnes, and A. I. Faden
Activation of Metabotropic Glutamate Receptor 5 Modulates Microglial Reactivity and Neurotoxicity by Inhibiting NADPH Oxidase
J. Biol. Chem., June 5, 2009; 284(23): 15629 - 15639.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|