Redox regulation of NF ‐κB p50 and M1 polarization in microglia
2014; Wiley; Volume: 63; Issue: 3 Linguagem: Inglês
10.1002/glia.22762
ISSN1098-1136
AutoresThomas Taetzsch, Shannon Levesque, Constance McGraw, Savannah Brookins, Rafy Luqa, Marcelo G. Bonini, Ronald P. Mason, Unsong Oh, Michelle L. Block,
Tópico(s)Immune Response and Inflammation
ResumoRedox‐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 H 2 O 2 showed altered NF‐κB p50 protein–protein interactions, decreased NF‐κB p50 DNA binding, and augmented late‐stage TNFα expression, indicating that H 2 O 2 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. GLIA 2015;63:423–440
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