title: Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways.
abstract: Activation of microglia cells in the brain contributes to neurodegenerative processes promoted by many neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO). Reactive oxygen species (ROS) actively affect microglia-associated neurodegenerative diseases through their role as pro-inflammatory molecules and modulators of pro-inflammatory processes. Although the ROS which involved in microglia activation are thought to be generated primarily by NADPH oxidase (NOX) and involved in the immune response, mitochondrial ROS have also been proposed as important regulators of the inflammatory response in the innate immune system. However, the role of mitochondrial ROS in microglial activation has yet to be fully elucidated. In this study, we demonstrate that inhibition of mitochondrial ROS by treatment with Mito-TEMPO effectively suppressed the level of mitochondrial and intracellular ROS. Mito-TEMPO treatment also significantly prevented LPS-induced increase in the TNF-α, IL-1β, IL-6, iNOS and Cox-2 in BV-2 and primary microglia cells. Furthermore, LPS-induced suppression of mitochondrial ROS generation not only affected LPS-stimulated activation of MAPKs, including ERK, JNK, and p38, but also regulated IκB activation and NF-κB nuclear localization. These results indicate that mitochondria constitute a major source of ROS generation in LPS-mediated activated microglia cells. Additionally, suppression of LPS-induced mitochondrial ROS plays a role in modulating the production of pro-inflammatory mediators by preventing MAPK and NF-κB activation in microglia cells. Our findings suggest that a potential strategy in the development of therapy for inflammation-associated degenerative neurological diseases involves targeting the regulation of mitochondrial ROS in microglial cells.
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Junghyung
authors.initials: J
authors.lastname: Park
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Ju-Sik
authors.initials: JS
authors.lastname: Min
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Un-Bin
authors.initials: UB
authors.lastname: Chae
authors.affiliation: Department of Biotechnology, Daegu University, Kyungsan, Republic of Korea.
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: School of Life Science and Biotechnology, Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Myung-Sook
authors.initials: MS
authors.lastname: Choi
authors.affiliation: Department of Animal Science, Division of Applied Life Science (BK21plus) and Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Il-Keun
authors.initials: IK
authors.lastname: Kong
authors.affiliation: National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do, Republic of Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Chang
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. Electronic address: lee1@knu.ac.kr.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C555916:MitoTEMPO; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: Lipopolysaccharide; MAPKs; Microglia; Mito-TEMPO; Mitochondrial ROS; NF-κB