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

Thomas Taetzsch, Shannon Levesque, Constance Mcgraw, Savannah Brookins, Rafy Luqa, Marcelo G. Bonini, Ronald P. Mason, Unsong Oh, Michelle L. Block

Research output: Contribution to journalArticle

43 Scopus citations

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 H2O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2O2 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.

Original languageEnglish (US)
Pages (from-to)423-440
Number of pages18
JournalGlia
Volume63
Issue number3
DOIs
StatePublished - Mar 1 2015

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Keywords

  • CNS
  • HO
  • Microglia
  • NF-κB p50
  • Redox signaling

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Taetzsch, T., Levesque, S., Mcgraw, C., Brookins, S., Luqa, R., Bonini, M. G., Mason, R. P., Oh, U., & Block, M. L. (2015). Redox regulation of NF-κB p50 and M1 polarization in microglia. Glia, 63(3), 423-440. https://doi.org/10.1002/glia.22762