Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Abstract

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-γ), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS+/+) or from iNOS knockout mice (iNOS-/-). We found an impairment of NSC cell proliferation in iNOS+/+ mixed cultures, which was not observed in iNOS-/- mixed cultures. Furthermore, the increased release of NO by activated iNOS+/+ microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP, cell proliferation and ERK signaling were restored to basal levels in iNOS+/+ mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 μM), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.

Cellular Senescence as the Causal Nexus of Aging

“…Interestingly, genetically induced progressive low grade chronic inflammation through knockout of the nfkb1 subunit of transcription factor NF-κB leads to telomere dysfunction, eventually causing senescence ( Jurk et al, 2014 ) and ultimately resulting in early onset of aging ( Bernal et al, 2014 ). A similar mechanism is evident with epidermal growth factor signaling dependent neural stem cell proliferation that is impaired by nitric oxide produced in response to inflammation ( Carreira et al, 2014 ).…”

H2S- and NO-Signaling Pathways in Alzheimer's Amyloid Vasculopathy: Synergism or Antagonism?

“…At the same time, endogenous production of NO downstream of RyR activation is required for the positive regulation of proliferation of hippocampal neural progenitor cells derived from embryonic mice (Yoneyama et al, 2011 ). However, impairment of neural stem cells proliferation due to NO-mediated nitration of the EGF receptor and suppression signaling through the ERK/MAPK pathway was reported (Carreira et al, 2014 ). Together, targeting H 2 S and NO as putative local regulators of neurogenesis within the neurogenic niches may represent a novel approach for restoration of brain cell proliferation and differentiation in AD (Figure 2 ).…”

Ultrasensitive gold micro-structured electrodes enabling the detection of extra-cellular long-lasting potentials in astrocytes populations

“…Primary mixed glial cultures were obtained from new-born C57Bl6/J mice with 0–3 days 60 . Briefly, after decapitation the brains were removed, and the meninges and cerebellum were discarded.…”