Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells

Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initiall...

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Main Authors: Dagmar Hildebrand, Mariel-Esther Eberle, Sabine Marie Wölfle, Franziska Egler, Delal Sahin, Aline Sähr, Konrad A. Bode, Klaus Heeg
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-06-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fimmu.2018.01224/full
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spelling doaj-9f7c45294ed547eaaaa5990ce705192a2020-11-25T00:29:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01224365346Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting CellsDagmar Hildebrand0Mariel-Esther Eberle1Sabine Marie Wölfle2Franziska Egler3Delal Sahin4Aline Sähr5Konrad A. Bode6Klaus Heeg7Klaus Heeg8Medical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyMedical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, GermanyGerman Center for Infection Research (DZIF), Brunswick, GermanyAntigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.https://www.frontiersin.org/article/10.3389/fimmu.2018.01224/fullsuppressive antigen-presenting cellmiRNAhsa-miR-99b/let-7e/miR-125a clustersignal transducer and activator of transcription 3programmed death-ligand 1indolamin-2,3-dioxygenase
collection DOAJ
language English
format Article
sources DOAJ
author Dagmar Hildebrand
Mariel-Esther Eberle
Sabine Marie Wölfle
Franziska Egler
Delal Sahin
Aline Sähr
Konrad A. Bode
Klaus Heeg
Klaus Heeg
spellingShingle Dagmar Hildebrand
Mariel-Esther Eberle
Sabine Marie Wölfle
Franziska Egler
Delal Sahin
Aline Sähr
Konrad A. Bode
Klaus Heeg
Klaus Heeg
Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
Frontiers in Immunology
suppressive antigen-presenting cell
miRNA
hsa-miR-99b/let-7e/miR-125a cluster
signal transducer and activator of transcription 3
programmed death-ligand 1
indolamin-2,3-dioxygenase
author_facet Dagmar Hildebrand
Mariel-Esther Eberle
Sabine Marie Wölfle
Franziska Egler
Delal Sahin
Aline Sähr
Konrad A. Bode
Klaus Heeg
Klaus Heeg
author_sort Dagmar Hildebrand
title Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
title_short Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
title_full Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
title_fullStr Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
title_full_unstemmed Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells
title_sort hsa-mir-99b/let-7e/mir-125a cluster regulates pathogen recognition receptor-stimulated suppressive antigen-presenting cells
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2018-06-01
description Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.
topic suppressive antigen-presenting cell
miRNA
hsa-miR-99b/let-7e/miR-125a cluster
signal transducer and activator of transcription 3
programmed death-ligand 1
indolamin-2,3-dioxygenase
url https://www.frontiersin.org/article/10.3389/fimmu.2018.01224/full
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