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

2014-10Journal article Open access
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dc.contributor.authorCarreira, Bruno P.
dc.contributor.authorMorte, Maria I.
dc.contributor.authorSantos, Ana I.
dc.contributor.authorLourenco, Ana S.
dc.contributor.authorAmbrosio, Antonio F.
dc.contributor.authorCarvalho, Caetana M.
dc.contributor.authorAraújo, Inês
dc.date.accessioned2018-12-07T14:58:09Z
dc.date.available2018-12-07T14:58:09Z
dc.date.issued2014-10
dc.description.abstractNeuroinflammation 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-gamma), 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 mu M), 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.
dc.description.sponsorshipFoundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.3389/fncel.2014.00343
dc.identifier.issn1662-5102
dc.identifier.urihttp://hdl.handle.net/10400.1/11882
dc.language.isoeng
dc.peerreviewedyes
dc.publisherFrontiers Research Foundation
dc.relationENHANCEMENT OF POST-INJURY NEUROGENESIS BY ANTI-INFLAMMATORY DRUGS AND NITRIC OXIDE
dc.relationEnhancement of endogenous neurogenesis by nitric oxide: identification of S-nitrosylation targets
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCentral-nervous-system
dc.subjectPeroxynitrite decomposition catalysts
dc.subjectSubventricular zone neurogenesis
dc.subjectAdult hippocampal neurogenesis
dc.subjectProgenitor cells
dc.subjectMitochondrial respiration
dc.subjectNeurotrophic factor
dc.subjectClick chemistry
dc.subjectPrecursor cells
dc.subjectMammalian brain
dc.titleNitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleENHANCEMENT OF POST-INJURY NEUROGENESIS BY ANTI-INFLAMMATORY DRUGS AND NITRIC OXIDE
oaire.awardTitleEnhancement of endogenous neurogenesis by nitric oxide: identification of S-nitrosylation targets
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F77903%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F79308%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FNEU-OSD%2F0473%2F2012/PT
oaire.citation.startPageUNSP 343
oaire.citation.titleFrontiers in Cellular Neuroscience
oaire.citation.volume8
oaire.fundingStreamSFRH
oaire.fundingStream3599-PPCDT
person.familyNameSantos
person.familyNameLourenço
person.familyNamePombinho de Araújo
person.givenNameAna Isabel
person.givenNameAna Sofia
person.givenNameInês Maria
person.identifier170713
person.identifierF-4703-2012
person.identifier.ciencia-idA31D-E831-28E8
person.identifier.ciencia-idD11F-D4CA-2947
person.identifier.orcid0000-0003-2070-0285
person.identifier.orcid0000-0003-2882-6026
person.identifier.orcid0000-0002-2438-0111
person.identifier.scopus-author-id55019179900
person.identifier.scopus-author-id56822397300
person.identifier.scopus-author-id56271084100
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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