SOD1 overexpression alters ROS production and reduces neurotoxic inflammatory signaling in microglial cells.
Activation of the oxidative burst is one of the earliest biochemical events in microglial activation, but it is not understood yet how free radicals participate in inflammatory signaling. To determine the role that specific reactive oxygen species play in microglial activation, the levels of SOD1 were manipulated in N9 murine microglia. Stable overexpression of SOD1 caused significant decreases in superoxide and nitric oxide production, with concurrent increases in hydrogen peroxide following LPS. However, LPS-induced activation of NFkappaB, and release of TNFalpha and IL-6 were significantly attenuated in SOD1 overexpressing cells, as was the ability of microglia to induce toxicity in cultured neurons. Conversely, acute inhibition of SOD1 with disulfiram was associated with increased nitric oxide and cytokine release, and increased neurotoxicity. Together, these data suggest that superoxide radicals in microglia play important roles in directing redox-sensitive inflammatory signaling and initiating neurotoxic inflammation.
Dimayuga
Filomena O
FO
Mn 222 Chandler Medical Center, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, United States.
Wang
Chunmei
C
Clark
Jordan M
JM
Dimayuga
Edgardo R
ER
Dimayuga
Vanessa M
VM
Bruce-Keller
Annadora J
AJ
D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D006861:Hydrogen Peroxide; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009498:Neurotoxins; D009569:Nitric Oxide; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse