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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Redox regulation of NF-κB p50 and M1 polarization in microglia
Thomas Taetzsch1, Shannon Levesque, Constance McGraw
1Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia.
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.
Insights
Oxidation of NF-κB p50 signals harmful microglial activation in brain diseases. Loss of this protein impairs the M1/M2 balance, causing CNS-specific chronic neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial activation is crucial in Central Nervous System (CNS) diseases.
- The role of reactive oxygen species (ROS) in programming microglial dysfunction remains unclear.
Purpose of the Study:
- To identify redox-signaling mechanisms regulating microglial polarization.
- To investigate the function of NF-κB p50 in neuroinflammation and microglial M1/M2 balance.
Main Methods:
- Oxidation of NF-κB p50 was analyzed as a marker for M1 microglial polarization.
- Studies involved exposing microglia to hydrogen peroxide (H2O2) and lipopolysaccharide (LPS).
- Experiments utilized NF-κB p50 knockout (NF-κB p50(-/-)) mice and wild-type (NF-κB p50(+/+)) mice, with and without spin-trap DMPO treatment.
Main Results:
- Oxidized NF-κB p50 was identified as a marker of dysfunctional M1 microglia.
- H2O2 impaired NF-κB p50 function, prolonging M1 activation and TNFα expression.
- NF-κB p50 deficiency led to disrupted M2 responses, impaired M1 resolution, and persistent neuroinflammation in mice.
- DMPO treatment had differential effects on TNFα production in wild-type versus knockout mice, highlighting NF-κB p50's role.
Conclusions:
- NF-κB p50 is a key redox-signaling regulator of the M1/M2 microglial balance.
- Loss of NF-κB p50 function confers CNS-specific vulnerability to chronic neuroinflammation.
- Understanding this mechanism offers potential therapeutic targets for CNS diseases driven by neuroinflammation.
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