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

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 (1mg/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.

Microglia antioxidant systems and redox signalling

“…However, curiously, treatment of gp91phox(À/À) mice with minocycline results in enhanced microglia activation and neuronal loss relative to wild-type mice also treated with minocycline (Hernandes et al, 2013). Disregarding non-cell-autonomous effects, these data, together with the observations of Block et al (Taetzsch et al, 2015), suggest that NOX2 activity can be required for anti-inflammatory effects in M2-activated microglia.…”

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

“…For instance, p50 homodimers suppressed the production of proinflammatory mediators (53) and upregulated anti-inflammatory cytokines, such as IL-10 (54). Moreover, they suppressed the classic macrophage proinflammatory response through inhibiting IFN-b and actively drove alternative macrophage (M2) polarization (55,56), which is crucial for resolving inflammation (57). Moreover, the absence of p50 has been shown to aggravate pulmonary inflammation in E. coli-induced pneumonia (58) as well as result in more profound hepatic inflammation and severe fibrosis in chronic liver injury (59).…”

Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

“…Modulation of microglial activation from the proinflammatory M1-like mode to pro-regenerative M2-like mode has been suggested as a therapeutic strategy in neuroinflammatory conditions [40,41]. In vitro and in vivo studies largely using LPS as classical inflammatory stimulus have demonstrated that Nfkb1 gene deficiency in macrophages and microglia impairs the shift from M1 to M2-type activation and thus, timely resolution of the inflammation [42,43]. This effect has been attributed to the inhibitory function of p50/p50 homodimers and p105 precursor protein.…”