Redox regulation of NF‐κB p50 and M1 polarization in microglia. Issue 3 (21st October 2014)

• Record Type: Journal Article
• Authors: Taetzsch, Thomas; Levesque, Shannon; McGraw, Constance; Brookins, Savannah; Luqa, Rafy; Bonini, Marcelo G.; Mason, Ronald P.; Oh, Unsong; Block, Michelle L.
• Is Part Of: Glia. Volume 63:Issue 3(2015:Mar.)
• Page Start: 423
• Page End: 440
• Publication Date: 2014-10-21
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22762
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 H<sub>2</sub>O<sub>2</sub> showed altered NF‐κB p50 protein–protein interactions, decreased NF‐κB p50 DNA binding, and augmented late‐stage TNFα expression, indicating that H<sub>2</sub>O<sub>2</sub> impairs NF‐κB p50 function and prolongs amplified M1 activation. NF‐κB p50<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>+/+</sup> mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF‐κB p50<sup>−/−</sup> 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</p> </abstract>