title: Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation.
abstract: Like macrophages, microglia are functionally polarized into different phenotypic activation states, referred as classical and alternative. The balance of the two phenotypes may be critical to ensure proper brain homeostasis, and may be altered in brain pathological states, such as Alzheimer's disease. We investigated the role of NADPH oxidase in microglial activation state using p47(phox) and gp91(phox) -deficient mice as well as apocynin, a NADPH oxidase inhibitor during neuroinflammation induced by an intracerebroventricular injection of LPS or Aβ₁₋₄₂. We showed that NADPH oxidase plays a critical role in the modulation of microglial phenotype and subsequent inflammatory response. We demonstrated that inhibition of NADPH oxidase or gene deletion of its functional p47(phox) subunit switched microglial activation from a classical to an alternative state in response to an inflammatory challenge. Moreover, we showed a shift in redox state towards an oxidized milieu and that subpopulations of microglia retain their detrimental phenotype in Alzheimer's disease brains. Microglia can change their activation phenotype depending on NADPH oxidase-dependent redox state of microenvironment. Inhibition of NADPH oxidase represents a promising neuroprotective approach to reduce oxidative stress and modulate microglial phenotype towards an alternative state.
authors: Molecular Neuroscience Unit, National Institutes of Health, Bethesda, Maryland, USA.
authors: Sang-Ho
authors: SH
authors: Choi
authors: Saba
authors: S
authors: Aid
authors: Hyung-Wook
authors: HW
authors: Kim
authors: Sharon H
authors: SH
authors: Jackson
authors: Francesca
authors: F
authors: Bosetti
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000098:Acetophenones / Q000627:therapeutic use; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000172:deficiency; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism*; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency
chemical_list: D000098:Acetophenones; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C105949:Pirb protein, mouse; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C056165:acetovanillone; D019255:NADPH Oxidases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C518330:RUVBL2 protein, mouse