PT  - JOURNAL ARTICLE
AU  - Lundahl, Mimmi L. E.
AU  - Mitermite, Morgane
AU  - Ryan, Dylan G.
AU  - Williams, Niamh C.
AU  - Yang, Ming
AU  - Lebre, Filipa
AU  - Gorman, Aoife L.
AU  - Stojkovic, Bojan
AU  - Frezza, Christian
AU  - Scanlan, Eoin M.
AU  - O’Neill, Luke A. J.
AU  - Gordon, Stephen V.
AU  - Lavelle, Ed C.
TI  - Macrophage Innate Training Induced by IL-4 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses
AID  - 10.1101/2021.10.12.463833
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.12.463833
4099  - http://biorxiv.org/content/early/2021/10/12/2021.10.12.463833.short
4100  - http://biorxiv.org/content/early/2021/10/12/2021.10.12.463833.full
AB  - Macrophages are key innate immune cells for determining the outcome of Mycobacterium tuberculosis infection. Polarization with IFNγ and LPS into the “classically activated” M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating the bacterium. 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 counterintuitively induces protective innate memory against mycobacterial challenge. This was associated with enhanced pro-inflammatory cytokine responses and killing capacity. Moreover, despite this switch towards a phenotype that is more akin to classical activation, IL-4 trained 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 trained macrophages. Lastly, this work identifies that IL-10 negatively regulates protective IL-4 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.Competing Interest StatementThe authors have declared no competing interest.