Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. (1st January 2015)

• Record Type: Journal Article
• Authors: Park, Junghyung; Min, Ju-Sik; Kim, Bokyung; Chae, Un-Bin; Yun, Jong Won; Choi, Myung-Sook; Kong, Il-Keun; Chang, Kyu-Tae; Lee, Dong-Seok
• Is Part Of: Neuroscience letters. Volume 584(2015)
• Page Start: 191
• Page End: 196
• Publication Date: 2015-01-01
• Subjects: cDNA complementary DNA -- Cox-2 cyclooxygenase-2 -- DMEM Dulbecco's modified Eagle's medium -- ERK extracellular signal-regulated kinase -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- IL interleukin -- iNOS inducible nitric oxide synthase -- IκB nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor -- JNK c-jun N-terminal kinase -- LPS lipopolysaccharide -- MAPK mitogen-activated protein kinase -- Mito-TEMPO (2-(2, 2, 6, 6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NLRP3 NLR family, pyrin domain containing 3 -- SOD superoxide dismutase -- TNF tumor necrosis factor; Microglia -- Lipopolysaccharide -- Mitochondrial ROS -- Mito-TEMPO -- MAPKs -- NF-κB; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2014.10.016
• Languages: English
• ISSNs: 0304-3940

Abstract

Graphical abstract: Highlights: Mito-TEMPO attenuates LPS-induced increase of mitochondrial ROS levels in microglia. Mito-TEMPO prevents elevated levels of intracellular ROS in activated microglia cells. Mito-TEMPO attenuates production of pro-inflammatory mediators by LPS. Mito-TEMPO suppresses LPS-induced MAPKs and NF-κB activation. 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.