Targeting angiotensin II type-1 receptor (AT1R) inhibits the harmful phenotype of plasmodium-specific CD8+ T cells during blood-stage malaria

Silva-Filho, J. L. , Caruso-Neves, C. and Pinheiro, A. A.S. (2017) Targeting angiotensin II type-1 receptor (AT1R) inhibits the harmful phenotype of plasmodium-specific CD8+ T cells during blood-stage malaria. Frontiers in Cellular and Infection Microbiology, 7, 42. (doi: 10.3389/fcimb.2017.00042) (PMID:28261571) (PMCID:PMC5311040)

[img] Text
252227.pdf - Published Version
Available under License Creative Commons Attribution.

6MB

Abstract

CD8+ 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 AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R 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 AT1R 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 (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R−/− OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R−/− 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-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8+ T cells during blood-stage malaria.

Item Type:Articles
Additional Information:This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (www.cnpq.br): 1. 57.3695/2008-3 AS, 2. 57.3767/2008-4 CC, 3. 471771/2013- 9 CC, 4. 456997/2014-8 AS, and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (www.faperj.br): 1. E-26/110.551/2010 CC, 2. 111681/2013 CC, 3. E-26/102.170/2013 AS, 4. E-26/201.197/2014 CC.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Da Silva Filho, Dr Joao
Authors: Silva-Filho, J. L., Caruso-Neves, C., and Pinheiro, A. A.S.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Frontiers in Cellular and Infection Microbiology
Publisher:Frontiers Media
ISSN:2235-2988
ISSN (Online):2235-2988
Copyright Holders:Copyright © 2017 Silva-Filho, Caruso-Neves and Pinheiro
First Published:First published in Frontiers in Cellular and Infection Microbiology 7: 42
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record