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TNF-alpha-induced microglia activation requires miR-342: impact on NF-kB signaling and neurotoxicity

2020Journal article Open access
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dc.contributor.authorBrás, João Paulo
dc.contributor.authorBravo, Joana
dc.contributor.authorFreitas, Jaime
dc.contributor.authorBarbosa, Mário Adolfo
dc.contributor.authorSantos, Susana Gomes
dc.contributor.authorSummavielle, Teresa
dc.date.accessioned2022-01-12T11:35:45Z
dc.date.available2022-01-12T11:35:45Z
dc.date.issued2020
dc.description.abstractGrowing evidences suggest that sustained neuroinflammation, caused by microglia overactivation, is implicated in the development and aggravation of several neurological and psychiatric disorders. In some pathological conditions, microglia produce increased levels of cytotoxic and inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), which can reactivate microglia in a positive feedback mechanism. However, specific molecular mediators that can be effectively targeted to control TNF-α-mediated microglia overactivation, are yet to be uncovered. In this context, we aim to identify novel TNF-α-mediated micro(mi)RNAs and to dissect their roles in microglia activation, as well as to explore their impact on the cellular communication with neurons. A miRNA microarray, followed by RT-qPCR validation, was performed on TNF-α-stimulated primary rat microglia. Gain- and loss-of-function in vitro assays and proteomic analysis were used to dissect the role of miR-342 in microglia activation. Co-cultures of microglia with hippocampal neurons, using a microfluidic system, were performed to understand the impact on neurotoxicity. Stimulation of primary rat microglia with TNF-α led to an upregulation of Nos2, Tnf, and Il1b mRNAs. In addition, ph-NF-kB p65 levels were also increased. miRNA microarray analysis followed by RT-qPCR validation revealed that TNF-α stimulation induced the upregulation of miR-342. Interestingly, miR-342 overexpression in N9 microglia was sufficient to activate the NF-kB pathway by inhibiting BAG-1, leading to increased secretion of TNF-α and IL-1β. Conversely, miR-342 inhibition led to a strong decrease in the levels of these cytokines after TNF-α activation. In fact, both TNF-α-stimulated and miR-342-overexpressing microglia drastically affected neuron viability. Remarkably, increased levels of nitrites were detected in the supernatants of these co-cultures. Globally, our findings show that miR-342 is a crucial mediator of TNF-α-mediated microglia activation and a potential target to tackle microglia-driven neuroinflammation.pt_PT
dc.description.sponsorshipWe would like to thank Dr. João Relvas laboratory for the help with N9 microglia cell culture; Dr. Sofia Lamas for the guidance on the animal welfare and support with animal experiments (Animal facility, i3S); and to LC Sciences for the miRNA microarray data and analysis. The mass spectrometry technique was performed by Hugo Osório at the i3S Proteomics Scientific Platform with support from the Portuguese Mass Spectrometry Network, integrated in the National Roadmap of Research Infrastructures of Strategic Relevance (ROTEIRO/0028/2013; LISBOA-01–0145-FEDER-022125). This work was funded by project NORTE-01–0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). J.P.B. and J.B. are supported by FCT–Fundação para a Ciência e Tecnologia, through BiotechHealth PhD program fellowship (PD/BD/135490/2018) and Areas of Basic and Applied Biology PhD program fellowship (PD/BD/135450/2017), respectively.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBrás, J. P., Bravo, J., Freitas, J., Barbosa, M. A., Santos, S. G., Summavielle, T., & Almeida, M. I. (2020). TNF-alpha-induced microglia activation requires miR-342: Impact on NF-kB signaling and neurotoxicity. Cell Death & Disease, 11(6), Artigo 6. https://doi.org/10.1038/s41419-020-2626-6
dc.identifier.doi10.1038/s41419-020-2626-6pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.22/19421
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationROTEIRO/0028/2013; LISBOA-01–0145-FEDER-022125pt_PT
dc.relationNORTE-01–0145-FEDER-000012pt_PT
dc.relationPsychostimulants and neuroinflammation: finding critical prayers in a crosstalk between glial cells and neuros
dc.relation.publisherversionhttps://www.nature.com/articles/s41419-020-2626-6pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectEnzyme-linked immunosorbent assay (ELISA)pt_PT
dc.subjectMixed glial cellspt_PT
dc.subjectPrimary microgliapt_PT
dc.subjectN9 microglial cellspt_PT
dc.subjectTNF-alpha-induced microglia activationpt_PT
dc.subjectmiR-342pt_PT
dc.titleTNF-alpha-induced microglia activation requires miR-342: impact on NF-kB signaling and neurotoxicitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePsychostimulants and neuroinflammation: finding critical prayers in a crosstalk between glial cells and neuros
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/PD%2FBD%2F135490%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/PD%2FBD%2F135450%2F2017/PT
oaire.citation.issue6pt_PT
oaire.citation.titleCell Death & Diseasept_PT
oaire.citation.volume11pt_PT
oaire.fundingStreamPOR_NORTE
oaire.fundingStreamPOR_NORTE
person.familyNameSummavielle
person.givenNameTeresa
person.identifier677706
person.identifier.ciencia-idC41E-0816-5C85
person.identifier.orcid0000-0003-2548-6281
person.identifier.ridC-9776-2012
person.identifier.scopus-author-id6603092949
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
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication207ee2de-85a0-4144-9e7e-b376c600e065
relation.isAuthorOfPublication.latestForDiscovery207ee2de-85a0-4144-9e7e-b376c600e065
relation.isProjectOfPublication97b5e465-0c95-4af8-8327-a2b5db2de7b4
relation.isProjectOfPublication02600fa1-12c5-4f33-978e-0239cc635135
relation.isProjectOfPublication.latestForDiscovery02600fa1-12c5-4f33-978e-0239cc635135

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