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Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses
Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, ‘alternatively...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9555863/ https://www.ncbi.nlm.nih.gov/pubmed/36173104 http://dx.doi.org/10.7554/eLife.74690 |
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author | Lundahl, Mimmi LE Mitermite, Morgane Ryan, Dylan Gerard Case, Sarah Williams, Niamh C Yang, Ming Lynch, Roisin I Lagan, Eimear Lebre, Filipa M Gorman, Aoife L Stojkovic, Bojan Bracken, Adrian P Frezza, Christian Sheedy, Frederick J Scanlan, Eoin M O'Neill, Luke AJ Gordon, Stephen V Lavelle, Ed C |
author_facet | Lundahl, Mimmi LE Mitermite, Morgane Ryan, Dylan Gerard Case, Sarah Williams, Niamh C Yang, Ming Lynch, Roisin I Lagan, Eimear Lebre, Filipa M Gorman, Aoife L Stojkovic, Bojan Bracken, Adrian P Frezza, Christian Sheedy, Frederick J Scanlan, Eoin M O'Neill, Luke AJ Gordon, Stephen V Lavelle, Ed C |
author_sort | Lundahl, Mimmi LE |
collection | PubMed |
description | Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, ‘alternatively activated’ M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection. |
format | Online Article Text |
id | pubmed-9555863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-95558632022-10-13 Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses Lundahl, Mimmi LE Mitermite, Morgane Ryan, Dylan Gerard Case, Sarah Williams, Niamh C Yang, Ming Lynch, Roisin I Lagan, Eimear Lebre, Filipa M Gorman, Aoife L Stojkovic, Bojan Bracken, Adrian P Frezza, Christian Sheedy, Frederick J Scanlan, Eoin M O'Neill, Luke AJ Gordon, Stephen V Lavelle, Ed C eLife Immunology and Inflammation Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, ‘alternatively activated’ M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection. eLife Sciences Publications, Ltd 2022-09-29 /pmc/articles/PMC9555863/ /pubmed/36173104 http://dx.doi.org/10.7554/eLife.74690 Text en © 2022, Lundahl et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Lundahl, Mimmi LE Mitermite, Morgane Ryan, Dylan Gerard Case, Sarah Williams, Niamh C Yang, Ming Lynch, Roisin I Lagan, Eimear Lebre, Filipa M Gorman, Aoife L Stojkovic, Bojan Bracken, Adrian P Frezza, Christian Sheedy, Frederick J Scanlan, Eoin M O'Neill, Luke AJ Gordon, Stephen V Lavelle, Ed C Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title | Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title_full | Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title_fullStr | Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title_full_unstemmed | Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title_short | Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses |
title_sort | macrophage innate training induced by il-4 and il-13 activation enhances oxphos driven anti-mycobacterial responses |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9555863/ https://www.ncbi.nlm.nih.gov/pubmed/36173104 http://dx.doi.org/10.7554/eLife.74690 |
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