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Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis
Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083984/ https://www.ncbi.nlm.nih.gov/pubmed/33936102 http://dx.doi.org/10.3389/fimmu.2021.664371 |
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author | El-Far, Mohamed Durand, Madeleine Turcotte, Isabelle Larouche-Anctil, Etienne Sylla, Mohamed Zaidan, Sarah Chartrand-Lefebvre, Carl Bunet, Rémi Ramani, Hardik Sadouni, Manel Boldeanu, Irina Chamberland, Annie Lesage, Sylvie Baril, Jean-Guy Trottier, Benoit Thomas, Réjean Gonzalez, Emmanuel Filali-Mouhim, Ali Goulet, Jean-Philippe Martinson, Jeffrey A. Kassaye, Seble Karim, Roksana Kizer, Jorge R. French, Audrey L. Gange, Stephen J. Ancuta, Petronela Routy, Jean-Pierre Hanna, David B. Kaplan, Robert C. Chomont, Nicolas Landay, Alan L. Tremblay, Cécile L. |
author_facet | El-Far, Mohamed Durand, Madeleine Turcotte, Isabelle Larouche-Anctil, Etienne Sylla, Mohamed Zaidan, Sarah Chartrand-Lefebvre, Carl Bunet, Rémi Ramani, Hardik Sadouni, Manel Boldeanu, Irina Chamberland, Annie Lesage, Sylvie Baril, Jean-Guy Trottier, Benoit Thomas, Réjean Gonzalez, Emmanuel Filali-Mouhim, Ali Goulet, Jean-Philippe Martinson, Jeffrey A. Kassaye, Seble Karim, Roksana Kizer, Jorge R. French, Audrey L. Gange, Stephen J. Ancuta, Petronela Routy, Jean-Pierre Hanna, David B. Kaplan, Robert C. Chomont, Nicolas Landay, Alan L. Tremblay, Cécile L. |
author_sort | El-Far, Mohamed |
collection | PubMed |
description | Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH. |
format | Online Article Text |
id | pubmed-8083984 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80839842021-04-30 Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis El-Far, Mohamed Durand, Madeleine Turcotte, Isabelle Larouche-Anctil, Etienne Sylla, Mohamed Zaidan, Sarah Chartrand-Lefebvre, Carl Bunet, Rémi Ramani, Hardik Sadouni, Manel Boldeanu, Irina Chamberland, Annie Lesage, Sylvie Baril, Jean-Guy Trottier, Benoit Thomas, Réjean Gonzalez, Emmanuel Filali-Mouhim, Ali Goulet, Jean-Philippe Martinson, Jeffrey A. Kassaye, Seble Karim, Roksana Kizer, Jorge R. French, Audrey L. Gange, Stephen J. Ancuta, Petronela Routy, Jean-Pierre Hanna, David B. Kaplan, Robert C. Chomont, Nicolas Landay, Alan L. Tremblay, Cécile L. Front Immunol Immunology Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH. Frontiers Media S.A. 2021-04-15 /pmc/articles/PMC8083984/ /pubmed/33936102 http://dx.doi.org/10.3389/fimmu.2021.664371 Text en Copyright © 2021 El-Far, Durand, Turcotte, Larouche-Anctil, Sylla, Zaidan, Chartrand-Lefebvre, Bunet, Ramani, Sadouni, Boldeanu, Chamberland, Lesage, Baril, Trottier, Thomas, Gonzalez, Filali-Mouhim, Goulet, Martinson, Kassaye, Karim, Kizer, French, Gange, Ancuta, Routy, Hanna, Kaplan, Chomont, Landay and Tremblay https://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) and the copyright owner(s) 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 | Immunology El-Far, Mohamed Durand, Madeleine Turcotte, Isabelle Larouche-Anctil, Etienne Sylla, Mohamed Zaidan, Sarah Chartrand-Lefebvre, Carl Bunet, Rémi Ramani, Hardik Sadouni, Manel Boldeanu, Irina Chamberland, Annie Lesage, Sylvie Baril, Jean-Guy Trottier, Benoit Thomas, Réjean Gonzalez, Emmanuel Filali-Mouhim, Ali Goulet, Jean-Philippe Martinson, Jeffrey A. Kassaye, Seble Karim, Roksana Kizer, Jorge R. French, Audrey L. Gange, Stephen J. Ancuta, Petronela Routy, Jean-Pierre Hanna, David B. Kaplan, Robert C. Chomont, Nicolas Landay, Alan L. Tremblay, Cécile L. Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title | Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title_full | Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title_fullStr | Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title_full_unstemmed | Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title_short | Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis |
title_sort | upregulated il-32 expression and reduced gut short chain fatty acid caproic acid in people living with hiv with subclinical atherosclerosis |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083984/ https://www.ncbi.nlm.nih.gov/pubmed/33936102 http://dx.doi.org/10.3389/fimmu.2021.664371 |
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