TY - JOUR TI - Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses AU - Lundahl, Mimmi LE AU - Mitermite, Morgane AU - Ryan, Dylan Gerard AU - Case, Sarah AU - Williams, Niamh C AU - Yang, Ming AU - Lynch, Roisin I AU - Lagan, Eimear AU - Lebre, Filipa M AU - Gorman, Aoife L AU - Stojkovic, Bojan AU - Bracken, Adrian P AU - Frezza, Christian AU - Sheedy, Frederick J AU - Scanlan, Eoin M AU - O'Neill, Luke AJ AU - Gordon, Stephen V AU - Lavelle, Ed C A2 - Yona, Simon A2 - Rath, Satyajit VL - 11 PY - 2022 DA - 2022/09/29 SP - e74690 C1 - eLife 2022;11:e74690 DO - 10.7554/eLife.74690 UR - https://doi.org/10.7554/eLife.74690 AB - 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. KW - macrophages KW - innate immunity KW - mycobacterium tuberculosis KW - cytokine KW - immunometabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -