Cargando…

Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria

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 AT(1) (AT(1)R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previousl...

Descripción completa

Detalles Bibliográficos
Autores principales: Silva-Filho, João L., Caruso-Neves, Celso, Pinheiro, Ana A. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311040/
https://www.ncbi.nlm.nih.gov/pubmed/28261571
http://dx.doi.org/10.3389/fcimb.2017.00042
_version_ 1782507955628802048
author Silva-Filho, João L.
Caruso-Neves, Celso
Pinheiro, Ana A. S.
author_facet Silva-Filho, João L.
Caruso-Neves, Celso
Pinheiro, Ana A. S.
author_sort Silva-Filho, João L.
collection PubMed
description 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 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/AT(1)R 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 AT(1)R(−/−) 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-2Rα 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, AT(1)R(−/−) 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 AT(1)R-induced harmful phenotype of Plasmodium-specific CD8(+) T cells during blood-stage malaria.
format Online
Article
Text
id pubmed-5311040
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-53110402017-03-03 Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria Silva-Filho, João L. Caruso-Neves, Celso Pinheiro, Ana A. S. Front Cell Infect Microbiol Microbiology 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 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/AT(1)R 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 AT(1)R(−/−) 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-2Rα 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, AT(1)R(−/−) 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 AT(1)R-induced harmful phenotype of Plasmodium-specific CD8(+) T cells during blood-stage malaria. Frontiers Media S.A. 2017-02-16 /pmc/articles/PMC5311040/ /pubmed/28261571 http://dx.doi.org/10.3389/fcimb.2017.00042 Text en Copyright © 2017 Silva-Filho, Caruso-Neves and Pinheiro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Silva-Filho, João L.
Caruso-Neves, Celso
Pinheiro, Ana A. S.
Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title_full Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title_fullStr Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title_full_unstemmed Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title_short Targeting Angiotensin II Type-1 Receptor (AT(1)R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria
title_sort targeting angiotensin ii type-1 receptor (at(1)r) inhibits the harmful phenotype of plasmodium-specific cd8(+) t cells during blood-stage malaria
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311040/
https://www.ncbi.nlm.nih.gov/pubmed/28261571
http://dx.doi.org/10.3389/fcimb.2017.00042
work_keys_str_mv AT silvafilhojoaol targetingangiotensiniitype1receptorat1rinhibitstheharmfulphenotypeofplasmodiumspecificcd8tcellsduringbloodstagemalaria
AT carusonevescelso targetingangiotensiniitype1receptorat1rinhibitstheharmfulphenotypeofplasmodiumspecificcd8tcellsduringbloodstagemalaria
AT pinheiroanaas targetingangiotensiniitype1receptorat1rinhibitstheharmfulphenotypeofplasmodiumspecificcd8tcellsduringbloodstagemalaria