Targeting Angiotensin Ii Type-1 Receptor (at(1)r) Inhibits The Harmful Phenotype Of Plasmodium-specific Cd8(+) T Cells During Blood-stage Malaria

dc.creatorSilva-Filho
dc.creatorJoao L.; Caruso-Neves
dc.creatorCelso; Pinheiro
dc.creatorAna A. S.
dc.date2017
dc.datefev
dc.date2017-11-13T13:45:21Z
dc.date2017-11-13T13:45:21Z
dc.date.accessioned2018-03-29T06:00:02Z
dc.date.available2018-03-29T06:00:02Z
dc.identifierFrontiers In Cellular And Infection Microbiology. Frontiers Media Sa, v. 7, p. , 2017.
dc.identifier2235-2988
dc.identifierWOS:000394184900001
dc.identifier10.3389/fcimb.2017.00042
dc.identifierhttp://journal.frontiersin.org/article/10.3389/fcimb.2017.00042/full
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/328991
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1366016
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionCD8(+) T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT(1) (AT(1)R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT(1)R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT(1)R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT(1)R in inducing the pathogenic activity of Plasmodium-specific CD8(+) T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8(+) T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R(-/-) Plasmodium-specific CD8(+) T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8(+) T cells were treated with losartan (AT(1)R antagonist) or captopril (ACE inhibitor). Both, AT(1)R(-/-) OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2R? expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT(1)R-/- OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R(-/-) OT-I cells produce lower amounts of IFN-gamma and TNF-alpha and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT(1)R-induced harmful phenotype of Plasmodium-specific CD8(+) T cells during blood-stage malaria.
dc.description7
dc.descriptionConselho Nacional de Desenvolvimento Cientifico e Tecnologico [57.3695/2008-3, 57.3767/2008-4, 471771/2013-9, 456997/2014-8]
dc.descriptionFundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro [E-26/110.551/2010, 111681/2013, E-26/102.170/2013, E-26/201.197/2014]
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.languageEnglish
dc.publisherFrontiers Media SA
dc.publisherLausanne
dc.relationFrontiers in Cellular and Infection Microbiology
dc.rightsaberto
dc.sourceWOS
dc.subjectAngiotensin
dc.subjectAt(1) Receptor
dc.subjectCd8(+) T Cells
dc.subjectBlood-stage
dc.subjectMalaria
dc.titleTargeting Angiotensin Ii Type-1 Receptor (at(1)r) Inhibits The Harmful Phenotype Of Plasmodium-specific Cd8(+) T Cells During Blood-stage Malaria
dc.typeArtículos de revistas


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