| Title: |
Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses. |
| Authors: |
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 |
| Source: |
essn: 2050-084X ; nlmid: 101579614 |
| Publisher Information: |
eLife; //doi.org/10.7554/elife.74690 |
| Publication Year: |
2022 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
cytokine; immunology; immunometabolism; inflammation; innate immunity; macrophages; mouse; mycobacterium tuberculosis; Animals; Cytokines; Glucose; Humans; Interleukin-10; Interleukin-13; Interleukin-4; Lipopolysaccharides; Macrophage Activation; Mice; Oligomycins; Oxidative Phosphorylation |
| Description: |
Funder: Trinity College Dublin ; 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
PMC9555863; https://www.repository.cam.ac.uk/handle/1810/342673 |
| DOI: |
10.17863/CAM.90088 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/342673; https://doi.org/10.17863/CAM.90088 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.56756CED |
| Database: |
BASE |