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Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis
Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553556/ https://www.ncbi.nlm.nih.gov/pubmed/31167948 http://dx.doi.org/10.1128/mSphere.00327-19 |
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author | Kim, Elliot W. De Leon, Avelino Jiang, Zhichun Radu, Roxana A. Martineau, Adrian R. Chan, Edward D. Bai, Xiyuan Su, Wen-Lin Montoya, Dennis J. Modlin, Robert L. Liu, Philip T. |
author_facet | Kim, Elliot W. De Leon, Avelino Jiang, Zhichun Radu, Roxana A. Martineau, Adrian R. Chan, Edward D. Bai, Xiyuan Su, Wen-Lin Montoya, Dennis J. Modlin, Robert L. Liu, Philip T. |
author_sort | Kim, Elliot W. |
collection | PubMed |
description | Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2 (NPC2)-dependent antimicrobial response against Mycobacterium tuberculosis, we investigated the mechanism by which the immune system converts retinol into ATRA at the site of infection. We demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived dendritic cells (DCs), but not macrophages, express enzymes in the vitamin A metabolic pathway, including aldehyde dehydrogenase 1 family, member a2 (ALDH1A2) and short-chain dehydrogenase/reductase family, member 9 (DHRS9), enzymes capable of the two-step conversion of retinol into ATRA, which is subsequently released from the cell. Additionally, mRNA and protein expression levels of ALDH1A2 and DC marker CD1B were lower in tuberculosis lung tissues than in normal lung. The conditioned medium from DCs cultured with retinol stimulated antimicrobial activity from M. tuberculosis-infected macrophages, as well as the expression of NPC2 in monocytes, which was blocked by specific inhibitors, including retinoic acid receptor inhibitor (RARi) or N,N-diethylaminobenzaldehyde (DEAB), an ALDH1A2 inhibitor. These results indicate that metabolism of vitamin A by DCs transactivates macrophage antimicrobial responses. IMPORTANCE Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide. One factor that contributes to the success of the microbe is the deficiency in immunomodulatory nutrients, such as vitamin A (retinol), which are prevalent in areas where TB is endemic. Clinical trials show that restoration of systemic retinol levels in active TB patients is ineffective in mitigating the disease; however, laboratory studies demonstrate that activation of the vitamin A pathway in Mycobacterium tuberculosis-infected macrophages triggers an antimicrobial response. Therefore, the goal of this study was to determine the link between host retinol levels and retinoic acid-mediated antimicrobial responses against M. tuberculosis. By combining established in vitro models with in situ studies of lung tissue from TB patients, this study demonstrates that the innate immune system utilizes transcellular metabolism leading to activation between dendritic cells and macrophages as a means to combat the pathogen. |
format | Online Article Text |
id | pubmed-6553556 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-65535562019-06-14 Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis Kim, Elliot W. De Leon, Avelino Jiang, Zhichun Radu, Roxana A. Martineau, Adrian R. Chan, Edward D. Bai, Xiyuan Su, Wen-Lin Montoya, Dennis J. Modlin, Robert L. Liu, Philip T. mSphere Research Article Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2 (NPC2)-dependent antimicrobial response against Mycobacterium tuberculosis, we investigated the mechanism by which the immune system converts retinol into ATRA at the site of infection. We demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived dendritic cells (DCs), but not macrophages, express enzymes in the vitamin A metabolic pathway, including aldehyde dehydrogenase 1 family, member a2 (ALDH1A2) and short-chain dehydrogenase/reductase family, member 9 (DHRS9), enzymes capable of the two-step conversion of retinol into ATRA, which is subsequently released from the cell. Additionally, mRNA and protein expression levels of ALDH1A2 and DC marker CD1B were lower in tuberculosis lung tissues than in normal lung. The conditioned medium from DCs cultured with retinol stimulated antimicrobial activity from M. tuberculosis-infected macrophages, as well as the expression of NPC2 in monocytes, which was blocked by specific inhibitors, including retinoic acid receptor inhibitor (RARi) or N,N-diethylaminobenzaldehyde (DEAB), an ALDH1A2 inhibitor. These results indicate that metabolism of vitamin A by DCs transactivates macrophage antimicrobial responses. IMPORTANCE Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide. One factor that contributes to the success of the microbe is the deficiency in immunomodulatory nutrients, such as vitamin A (retinol), which are prevalent in areas where TB is endemic. Clinical trials show that restoration of systemic retinol levels in active TB patients is ineffective in mitigating the disease; however, laboratory studies demonstrate that activation of the vitamin A pathway in Mycobacterium tuberculosis-infected macrophages triggers an antimicrobial response. Therefore, the goal of this study was to determine the link between host retinol levels and retinoic acid-mediated antimicrobial responses against M. tuberculosis. By combining established in vitro models with in situ studies of lung tissue from TB patients, this study demonstrates that the innate immune system utilizes transcellular metabolism leading to activation between dendritic cells and macrophages as a means to combat the pathogen. American Society for Microbiology 2019-06-05 /pmc/articles/PMC6553556/ /pubmed/31167948 http://dx.doi.org/10.1128/mSphere.00327-19 Text en Copyright © 2019 Kim et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Kim, Elliot W. De Leon, Avelino Jiang, Zhichun Radu, Roxana A. Martineau, Adrian R. Chan, Edward D. Bai, Xiyuan Su, Wen-Lin Montoya, Dennis J. Modlin, Robert L. Liu, Philip T. Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title | Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title_full | Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title_fullStr | Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title_full_unstemmed | Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title_short | Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis |
title_sort | vitamin a metabolism by dendritic cells triggers an antimicrobial response against mycobacterium tuberculosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553556/ https://www.ncbi.nlm.nih.gov/pubmed/31167948 http://dx.doi.org/10.1128/mSphere.00327-19 |
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