Macrophage Innate Training Induced by IL-4 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Macrophages are key innate immune cells for determining the outcome of Mycobacterium tuberculosis infection. Polarization with IFNg 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.