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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.

The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.

Genomics is revolutionizing biomedical research, medicine and healthcare globally in academic, public and industry sectors alike. Concrete examples around the world show that huge benefits for patients, society and economy can be accrued through effective and responsible genomic research and clinical applications. Unfortunately, Ireland has fallen behind and needs to act now in order to catch up. Here, we identify key issues that have resulted in Ireland lagging behind, describe how genomics can benefit Ireland and its people and outline the measures needed to make genomics work for Ireland and Irish patients. There is now an urgent need for a national genomics strategy that enables an effective, collaborative, responsible, well-regulated, and patient centred environment where genome research and clinical genomics can thrive. We present eight recommendations that could be the pillars of a national genomics health strategy.