title: Peroxiredoxin I is a ROS/p38 MAPK-dependent inducible antioxidant that regulates NF-κB-mediated iNOS induction and microglial activation.
abstract: Reactive oxygen species (ROS) function as modulators of pro-inflammatory processes in microglia-associated neurodegenerative diseases. However, little is known about the involvement of specific antioxidants in regulating the microglial redox status. Here, we demonstrated that peroxiredoxin (Prx) I activity was induced by lipopolysaccharide (LPS), but not paraquat and hydrogen peroxide, through activation of the ROS/p38 MAPK signal pathway, and participated in alleviating the microglial activation and generation of nitric oxide (NO). Interestingly, a null mutation of Prx I accelerated NF-κB-mediated iNOS induction and subsequent NO secretion in LPS-stimulated microglia. Furthermore, F4/80 expression as microglial activation marker was notably up-regulated in primary cultures of microglia, hippocampal sections, and cerebral cortex of 15-month-old Prx I(-/-) mouse. Taken together, the results of our study indicated that Prx I is an antioxidant that is up-regulated in a ROS/p38 MAPK-dependent manner and governs the progression of neuroinflammation by suppressing microglial activation. In addition, Prx I deficiency increased the nuclear translocation of NF-κB mediated-iNOS induction as pro-inflammatory mediators. The findings of our work suggest possible strategies for developing novel therapies to treat inflammation-associated degenerative neurological diseases by targeting the induction of Prx I in microglial cells.
authors.affiliation: National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea.
authors.forename: Sun-Uk
authors.initials: SU
authors.lastname: Kim
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Ju-Sik
authors.initials: JS
authors.lastname: Min
authors.forename: Hu-Nan
authors.initials: HN
authors.lastname: Sun
authors.forename: Ying-Hao
authors.initials: YH
authors.lastname: Han
authors.forename: Jin-Mei
authors.initials: JM
authors.lastname: Hua
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Lee
authors.forename: Sang-Rae
authors.initials: SR
authors.lastname: Lee
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Chang
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D009924:Organ Culture Techniques; D054464:Peroxiredoxins / Q000378:metabolism*; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases