| First Author | Taetzsch T | Year | 2015 |
| Journal | Glia | Volume | 63 |
| Issue | 3 | Pages | 423-40 |
| PubMed ID | 25331559 | Mgi Jnum | J:218287 |
| Mgi Id | MGI:5617117 | Doi | 10.1002/glia.22762 |
| Citation | Taetzsch T, et al. (2015) Redox regulation of NF-kappaB p50 and M1 polarization in microglia. Glia 63(3):423-40 |
| abstractText | 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-kappaB 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-kappaB p50 protein-protein interactions, decreased NF-kappaB p50 DNA binding, and augmented late-stage TNFalpha expression, indicating that H2 O2 impairs NF-kappaB p50 function and prolongs amplified M1 activation. NF-kappaB 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-kappaB 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 TNFalpha in the brain in NF-kappaB p50(+/+) mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFalpha production in NF-kappaB p50(-/-) mice, implicating a fundamental role for NF-kappaB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-kappaB 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. |
