Channeling macrophage polarization by using a selective translation inhibitor

The increasing problem of infectious diseases caused by antibiotic-resistant bacteria has intensified a search for novel host-directed therapies aimed at either boosting immune-mediated bacterial control or reducing immunopathology. Macrophages play central roles in eliminating pathogens as well as in tissue homeostasis and repair via alternative activation programs, M1-like and M2-like, respectively. Macrophages of both phenotypes are often present at the sites of chronic unresolved inflammation, such infectious granulomas and solid tumors, where the M2-like macrophages generate microenvironment conducive for pathogen survival or tumor progression. Interferon-gamma is a major cytokine that drives M1-like macrophage activation, which is essential for control of intracellular bacterial pathogens. To evaluate M1-like macrophage polarization as a broad therapeutic strategy, we searched for small molecules capable of enhancing effects of low concentrations of IFNγ on M1 macrophage polarization. We identified synthetic rocaglates that potentiated macrophages responses to low concentrations of IFNγ. Although known as potent translation inhibitors in tumor cell lines, in primary macrophages select rocaglates induced the upregulation of IRF1, a master regulator of IFNγ-activated pathways, stimulated autophagy and increased macrophage resilience to oxidative stress. In contrast, rocaglates inhibited macrophage responsiveness to IL-4, a prototypical activator of the M2-like phenotype. The M1-like macrophage programing by rocaglates was mechanistically linked to selective translation inhibition and modulation of MAP kinase network …