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- Title
Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase.
- Authors
Chéret, Cyril; Gervais, Annie; Lelli, Aurélia; Colin, Catherine; Amar, Lahouari; Ravassard, Philippe; Mallet, Jacques; Cumano, Ana; Krause, Karl-Heinz; Mallat, Michel
- 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 Rac⅛. 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.
- Subjects
MICROGLIA; PHAGOCYTES; IMMUNE system; MACROPHAGES; ANTINEOPLASTIC antibiotics; CELL-mediated cytotoxicity
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 46, p12039
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3568-08.2008