Redox regulation of NF-κB p50 and M1 polarization in microglia.
Glia
; 63(3): 423-40, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25331559
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Microglia
/
Subunidade p50 de NF-kappa B
/
Peróxido de Hidrogênio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article