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Argonaute-2 protects the neurovascular unit from damage caused by systemic inflammation

2022-01-06Artigo científico Acesso aberto
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dc.contributor.authorMachado-Pereira, Marta
dc.contributor.authorSaraiva, Cláudia
dc.contributor.authorBernardino, Liliana
dc.contributor.authorCristóvão, Ana C.
dc.contributor.authorFerreira, Raquel
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblBioMed Central (BMC)
dc.date.accessioned2022-01-26T03:31:41Z
dc.date.available2022-01-26T03:31:41Z
dc.date.issued2022-01-06
dc.descriptionFunding PPBI—Portuguese Platform of BioImaging, POCI-01-0145-FEDER-022122; FCT—Fundação para a Ciência e Tecnologia, UID/Multi/00709/2013, SFRH/ BD/137440/2018 (MMP), IF/00178/2015/CP1300/CT0001 (RF); FCT—L’Oréal— UNESCO Portugal for Women in Science (RF).
dc.description.abstractBackground: The brain vasculature plays a pivotal role in the inflammatory process by modulating the interaction between blood cells and the neurovascular unit. Argonaute-2 (Ago2) has been suggested as essential for endothelial survival but its role in the brain vasculature or in the endothelial–glial crosstalk has not been addressed. Thus, our aim was to clarify the significance of Ago2 in the inflammatory responses elicited by these cell types. Methods: Mouse primary cultures of brain endothelial cells, astrocytes and microglia were used to evaluate cellular responses to the modulation of Ago2. Exposure of microglia to endothelial cell-conditioned media was used to assess the potential for in vivo studies. Adult mice were injected intraperitoneally with lipopolysaccharide (LPS) (2 mg/kg) followed by three daily intraperitoneal injections of Ago2 (0.4 nM) to assess markers of endothelial disruption, glial reactivity and neuronal function. Results: Herein, we demonstrated that LPS activation disturbed the integrity of adherens junctions and downregulated Ago2 in primary brain endothelial cells. Exogenous treatment recovered intracellular Ago2 above control levels and recuperated vascular endothelial-cadherin expression, while downregulating LPS-induced nitric oxide release. Primary astrocytes did not show a significant change in Ago2 levels or response to the modulation of the Ago2 system, although endogenous Ago2 was shown to be critical in the maintenance of tumor necrosis factor-α basal levels. LPS-activated primary microglia overexpressed Ago2, and Ago2 silencing contained the inflammatory response to some extent, preventing interleukin-6 and nitric oxide release. Moreover, the secretome of Ago2-modulated brain endothelial cells had a protective effect over microglia. The intraperitoneal injection of LPS impaired blood–brain barrier and neuronal function, while triggering inflammation, and the subsequent systemic administration of Ago2 reduced or normalized endothelial, glial and neuronal markers of LPS damage. This outcome likely resulted from the direct action of Ago2 over the brain endothelium, which reestablished glial and neuronal function. Conclusions: Ago2 could be regarded as a putative therapeutic agent, or target, in the recuperation of the neurovascular unit in inflammatory conditions.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent2320453
dc.identifier.doi10.1186/s12974-021-02324-7
dc.identifier.otherPURE: 36216027
dc.identifier.otherPURE UUID: d469dcf4-7f72-4b24-ac5b-43b9fde28c5c
dc.identifier.otherScopus: 85122396471
dc.identifier.otherWOS: 000739961400001
dc.identifier.urihttp://hdl.handle.net/10362/131573
dc.identifier.urlhttps://www.scopus.com/pages/publications/85122396471
dc.language.isoeng
dc.peerreviewedyes
dc.subjectArgonaute-2
dc.subjectBrain endothelial cells
dc.subjectGlia
dc.subjectLipopolysaccharide
dc.subjectNeuroprotection
dc.subjectSecretome
dc.subjectGeneral Neuroscience
dc.subjectImmunology
dc.subjectNeurology
dc.subjectCellular and Molecular Neuroscience
dc.titleArgonaute-2 protects the neurovascular unit from damage caused by systemic inflammationen
dc.typejournal article
degois.publication.issue1
degois.publication.titleJournal of Neuroinflammation
degois.publication.volume19
dspace.entity.typePublication
rcaap.rightsopenAccess

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