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Redox regulation of NF-?B 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-?B 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-?B p50 protein-protein interactions, decreased NF-?B p50 DNA binding, and augmented late-stage TNF? expression, indicating that H2 O2 impairs NF-?B p50 function and prolongs amplified M1 activation. NF-?B 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-?B 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 TNF? in the brain in NF-?B p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNF? production in NF-?B p50(-/-) mice, implicating a fundamental role for NF-?B p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-?B 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.

SUBMITTER: Taetzsch T

PROVIDER: S-EPMC4322433 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Redox regulation of NF-κB p50 and M1 polarization in microglia.

Taetzsch Thomas T Levesque Shannon S McGraw Constance C Brookins Savannah S Luqa Rafy R Bonini Marcelo G MG Mason Ronald P RP Oh Unsong U Block Michelle L ML

Glia 20141021 3

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 ...[more]

PMID: 25331559

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Redox regulation of NF-?B p50 and M1 polarization in microglia.

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Redox regulation of NF-κB p50 and M1 polarization in microglia.

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