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Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations
Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contributi...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8914948/ https://www.ncbi.nlm.nih.gov/pubmed/35281062 http://dx.doi.org/10.3389/fimmu.2022.794776 |
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author | Pang, Ee Shan Daraj, Ghazal Balka, Katherine R. De Nardo, Dominic Macri, Christophe Hochrein, Hubertus Masterman, Kelly-Anne Tan, Peck S. Shoppee, Angus Magill, Zoe Jahan, Nazneen Bafit, Mariam Zhan, Yifan Kile, Benjamin T. Lawlor, Kate E. Radford, Kristen J. Wright, Mark D. O’Keeffe, Meredith |
author_facet | Pang, Ee Shan Daraj, Ghazal Balka, Katherine R. De Nardo, Dominic Macri, Christophe Hochrein, Hubertus Masterman, Kelly-Anne Tan, Peck S. Shoppee, Angus Magill, Zoe Jahan, Nazneen Bafit, Mariam Zhan, Yifan Kile, Benjamin T. Lawlor, Kate E. Radford, Kristen J. Wright, Mark D. O’Keeffe, Meredith |
author_sort | Pang, Ee Shan |
collection | PubMed |
description | Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes. |
format | Online Article Text |
id | pubmed-8914948 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89149482022-03-12 Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations Pang, Ee Shan Daraj, Ghazal Balka, Katherine R. De Nardo, Dominic Macri, Christophe Hochrein, Hubertus Masterman, Kelly-Anne Tan, Peck S. Shoppee, Angus Magill, Zoe Jahan, Nazneen Bafit, Mariam Zhan, Yifan Kile, Benjamin T. Lawlor, Kate E. Radford, Kristen J. Wright, Mark D. O’Keeffe, Meredith Front Immunol Immunology Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes. Frontiers Media S.A. 2022-02-25 /pmc/articles/PMC8914948/ /pubmed/35281062 http://dx.doi.org/10.3389/fimmu.2022.794776 Text en Copyright © 2022 Pang, Daraj, Balka, De Nardo, Macri, Hochrein, Masterman, Tan, Shoppee, Magill, Jahan, Bafit, Zhan, Kile, Lawlor, Radford, Wright and O’Keeffe 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 Pang, Ee Shan Daraj, Ghazal Balka, Katherine R. De Nardo, Dominic Macri, Christophe Hochrein, Hubertus Masterman, Kelly-Anne Tan, Peck S. Shoppee, Angus Magill, Zoe Jahan, Nazneen Bafit, Mariam Zhan, Yifan Kile, Benjamin T. Lawlor, Kate E. Radford, Kristen J. Wright, Mark D. O’Keeffe, Meredith Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title_full | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title_fullStr | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title_full_unstemmed | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title_short | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
title_sort | discordance in sting-induced activation and cell death between mouse and human dendritic cell populations |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8914948/ https://www.ncbi.nlm.nih.gov/pubmed/35281062 http://dx.doi.org/10.3389/fimmu.2022.794776 |
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