title: Redox regulation of NF-κB p50 and M1 polarization in microglia.
abstract: Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2 O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2 O2 impairs NF-κB p50 function and prolongs amplified M1 activation. NF-κB p50(-/-) mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1 mg/kg, IP) administration in the NF-κB p50(-/-) mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNFα in the brain in NF-κB p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF-κB p50(-/-) mice, implicating a fundamental role for NF-κB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-κB p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Taetzsch
authors.forename: Shannon
authors.initials: S
authors.lastname: Levesque
authors.forename: Constance
authors.initials: C
authors.lastname: McGraw
authors.forename: Savannah
authors.initials: S
authors.lastname: Brookins
authors.forename: Rafy
authors.initials: R
authors.lastname: Luqa
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.forename: Unsong
authors.initials: U
authors.lastname: Oh
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D015213:Neuroimmunomodulation / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D004247:DNA; D006861:Hydrogen Peroxide
keywords: CNS; H2O2; NF-κB p50; microglia; redox signaling