Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2017 |
| Outros Autores: | , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/25744 |
Resumo: | Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Belgian research funding agency FWO (grant G0D6817N) and by the FNRS (N.310030-173180) to NF and by the FNRS International cooperation (No IZRJZ3_164176/1) to NF and UGL. |
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Vivarini, Áislan de CarvalhoSilva, Teresa Cristina CalegariSaliba, Alessandra MattosBoaventura, Viviane SampaioCosta, Jaqueline FrançaCunha, Antonio Ricardo KhouriDierckx, TimTeixeira, Karina Luiza DiasFasel, NicolasBarral, Aldina Maria PradoBorges, Valéria MatosVan Weyenbergh, JohanLopes, Ulisses Gazos2018-04-10T17:44:39Z2018-04-10T17:44:39Z2017VIVARINI, A. C. et al. Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis. Frontiers in Immunology, v. 8, article 1127, 2017.1664-3224https://www.arca.fiocruz.br/handle/icict/2574410.3389/fimmu.2017.01127Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Belgian research funding agency FWO (grant G0D6817N) and by the FNRS (N.310030-173180) to NF and by the FNRS International cooperation (No IZRJZ3_164176/1) to NF and UGL.Federal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Center of Health Science. Laboratory of Molecular Parasitology. Rio de Janeiro, RJ, BrazilFederal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Center of Health Science. Laboratory of Molecular Parasitology. Rio de Janeiro, RJ, BrazilState University of Rio de Janeiro. Department of Microbiology, Immunology and Parasitology. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, BrasilRega Institute for Medical Research. KU Leuven. Department of Microbiology and Immunology. Leuven, BelgiumFederal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Center of Health Science. Laboratory of Molecular Parasitology. Rio de Janeiro, RJ, BrazilUniversity of Lausanne. Faculty of Biology and Medicine. Department of Biochemistry. Lausanne, SwitzerlandFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, BrasilRega Institute for Medical Research. KU Leuven. Department of Microbiology and Immunology. Leuven, BelgiumFederal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Center of Health Science. Laboratory of Molecular Parasitology. Rio de Janeiro, RJ, BrazilLeishmania parasites infect macrophages, causing a wide spectrum of human diseases, from cutaneous to visceral forms. In search of novel therapeutic targets, we performed comprehensivein vitroandex vivomapping of the signaling pathways upstream and downstream of antioxidant transcription factor [nuclear factor erythroid 2-related factor 2 (Nrf2)] in cutaneous leishmaniasis (CL), by combining functional assays in human and murine macrophages with a systems biology analysis ofin situ(skin biopsies) CL patient samples. First, we show the PKR pathway controls the expression and activation of Nrf2 inLeishmania amazonensisinfectionin vitro. Nrf2 activation also required PI3K/Akt signaling and autophagy mechanisms. Nrf2- or PKR/Akt-deficient macrophages exhibited increased levels of ROS/RNS and reduced expression ofSod1Nrf2-dependent gene and reduced parasite load.L. amazonensiscounteracted the Nrf2 inhibitor Keap1 through the upregulation of p62viaPKR. This Nrf2/Keap1 observation was confirmedin situin skin biopsies fromLeishmania-infected patients. Next, we explored theex vivotranscriptome in CL patients, as compared to healthy controls. We found the antioxidant response element/Nrf2 signaling pathway was significantly upregulated in CL, including downstream target p62.In silicoenrichment analysis confirmed upstream signaling by interferon and PI3K/Akt, and validated ourin vitrofindings. Our integratedin vitro, ex vivo, andin silicoapproach establish Nrf2 as a central player in human cutaneous leishmaniasis and reveal Nrf2/PKR crosstalk and PI3K/Akt pathways as potential therapeutic targets.engFrontiers MediaLeishmaniaMacrófagoFator nuclearPKRSod1LeishmaniaMacrophageNuclear factor erythroid 2-related factor 2PKRSod1Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/25744/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALVivarini AC Systems Approach Reveals Nuclear Factor....pdfVivarini AC Systems Approach Reveals Nuclear 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| dc.title.pt_BR.fl_str_mv |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| title |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| spellingShingle |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis Vivarini, Áislan de Carvalho Leishmania Macrófago Fator nuclear PKR Sod1 Leishmania Macrophage Nuclear factor erythroid 2-related factor 2 PKR Sod1 |
| title_short |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| title_full |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| title_fullStr |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| title_full_unstemmed |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| title_sort |
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis |
| author |
Vivarini, Áislan de Carvalho |
| author_facet |
Vivarini, Áislan de Carvalho Silva, Teresa Cristina Calegari Saliba, Alessandra Mattos Boaventura, Viviane Sampaio Costa, Jaqueline França Cunha, Antonio Ricardo Khouri Dierckx, Tim Teixeira, Karina Luiza Dias Fasel, Nicolas Barral, Aldina Maria Prado Borges, Valéria Matos Van Weyenbergh, Johan Lopes, Ulisses Gazos |
| author_role |
author |
| author2 |
Silva, Teresa Cristina Calegari Saliba, Alessandra Mattos Boaventura, Viviane Sampaio Costa, Jaqueline França Cunha, Antonio Ricardo Khouri Dierckx, Tim Teixeira, Karina Luiza Dias Fasel, Nicolas Barral, Aldina Maria Prado Borges, Valéria Matos Van Weyenbergh, Johan Lopes, Ulisses Gazos |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Vivarini, Áislan de Carvalho Silva, Teresa Cristina Calegari Saliba, Alessandra Mattos Boaventura, Viviane Sampaio Costa, Jaqueline França Cunha, Antonio Ricardo Khouri Dierckx, Tim Teixeira, Karina Luiza Dias Fasel, Nicolas Barral, Aldina Maria Prado Borges, Valéria Matos Van Weyenbergh, Johan Lopes, Ulisses Gazos |
| dc.subject.other.pt_BR.fl_str_mv |
Leishmania Macrófago Fator nuclear PKR Sod1 |
| topic |
Leishmania Macrófago Fator nuclear PKR Sod1 Leishmania Macrophage Nuclear factor erythroid 2-related factor 2 PKR Sod1 |
| dc.subject.en.pt_BR.fl_str_mv |
Leishmania Macrophage Nuclear factor erythroid 2-related factor 2 PKR Sod1 |
| description |
Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Belgian research funding agency FWO (grant G0D6817N) and by the FNRS (N.310030-173180) to NF and by the FNRS International cooperation (No IZRJZ3_164176/1) to NF and UGL. |
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2017 |
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2017 |
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2018-04-10T17:44:39Z |
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2018-04-10T17:44:39Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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VIVARINI, A. C. et al. Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis. Frontiers in Immunology, v. 8, article 1127, 2017. |
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https://www.arca.fiocruz.br/handle/icict/25744 |
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1664-3224 |
| dc.identifier.doi.none.fl_str_mv |
10.3389/fimmu.2017.01127 |
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VIVARINI, A. C. et al. Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis. Frontiers in Immunology, v. 8, article 1127, 2017. 1664-3224 10.3389/fimmu.2017.01127 |
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Frontiers Media |
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Frontiers Media |
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