Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT 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-Pic...

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Autores principales:	Elliot W. Kim, Avelino De Leon, Zhichun Jiang, Roxana A. Radu, Adrian R. Martineau, Edward D. Chan, Xiyuan Bai, Wen-Lin Su, Dennis J. Montoya, Robert L. Modlin, Philip T. Liu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Mycobacterium tuberculosis dendritic cells transcellular metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d742d0149e544e31881c00788a5150dc
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spelling	oai:doaj.org-article:d742d0149e544e31881c00788a5150dc2021-11-15T15:22:20ZVitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mSphere.00327-192379-5042https://doaj.org/article/d742d0149e544e31881c00788a5150dc2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00327-19https://doaj.org/toc/2379-5042ABSTRACT 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.Elliot W. KimAvelino De LeonZhichun JiangRoxana A. RaduAdrian R. MartineauEdward D. ChanXiyuan BaiWen-Lin SuDennis J. MontoyaRobert L. ModlinPhilip T. LiuAmerican Society for MicrobiologyarticleMycobacterium tuberculosisdendritic cellstranscellular metabolismMicrobiologyQR1-502ENmSphere, Vol 4, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis dendritic cells transcellular metabolism Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis dendritic cells transcellular metabolism Microbiology QR1-502 Elliot W. Kim Avelino De Leon Zhichun Jiang Roxana A. Radu Adrian R. Martineau Edward D. Chan Xiyuan Bai Wen-Lin Su Dennis J. Montoya Robert L. Modlin Philip T. Liu Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT 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	article
author	Elliot W. Kim Avelino De Leon Zhichun Jiang Roxana A. Radu Adrian R. Martineau Edward D. Chan Xiyuan Bai Wen-Lin Su Dennis J. Montoya Robert L. Modlin Philip T. Liu
author_facet	Elliot W. Kim Avelino De Leon Zhichun Jiang Roxana A. Radu Adrian R. Martineau Edward D. Chan Xiyuan Bai Wen-Lin Su Dennis J. Montoya Robert L. Modlin Philip T. Liu
author_sort	Elliot W. Kim
title	Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	vitamin a metabolism by dendritic cells triggers an antimicrobial response against <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d742d0149e544e31881c00788a5150dc
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Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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