Channeling macrophage polarization via selective translation inhibition by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Abstract

24The increasing problem of infectious diseases caused by antibiotic-resistant bacteria has 25 intensified a search for novel host-directed therapies aimed at either boosting immune-mediated 26 bacterial control or reducing immunopathology. Macrophages play central roles in eliminating 27 pathogens as well as in tissue homeostasis and repair via alternative activation programs, M1-28 like and M2-like, respectively. Macrophages of both phenotypes are often present at the sites of 29 chronic unresolved inflammation, such infectious granulomas and solid tumors, where the M2-30 like macrophages generate microenvironment conducive for pathogen survival or tumor 31 progression. 32Interferon-gamma is a major cytokine that drives M1-like macrophage activation, which 33 is essential for control of intracellular bacterial pathogens. To evaluate M1-like macrophage 34 polarization as a broad therapeutic strategy, we searched for small molecules capable of 35 enhancing effects of low concentrations of IFNγ on M1 macrophage polarization. We 36 identified synthetic rocaglates that potentiated macrophages responses to low concentrations 37 of IFNγ. Although known as potent translation inhibitors in tumor cell lines, in primary 38 macrophages select rocaglates induced the upregulation of IRF1, a master regulator of IFNγ 39-activated pathways, stimulated autophagy and increased macrophage resilience to oxidative 40 stress. In contrast, rocaglates inhibited macrophage responsiveness to IL-4, a prototypical 41 activator of the M2-like phenotype. The M1-like macrophage programing by rocaglates was 42 mechanistically linked to selective translation inhibition and modulation of MAP kinase 43 network. 44Thus, rocaglates represent a novel class of immunomodulators that can enforce 45 macrophage polarization towards the M1-like phenotype in complex microenvironments 46 3 associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., 47chronic bacterial infections, allergies and, possibly, certain tumors. 48 49 50 51The increasing problem of infectious diseases caused by antibiotic-resistant bacteria has 52 intensified a search for novel therapeutic approaches. Among them are host-directed therapies 53 aimed at either boosting immune-mediated bacterial control or reducing immunopathology, 54 broadly referred to as mechanisms of host resistance or disease tolerance, respectively (1). 55Many intracellular bacterial pathogens reside in macrophages, the very cells of innate immune 56 system whose major function is to eliminate invading pathogens. This paradox is enabled by 57 macrophages' plasticity, which successful pathogens exploit to create cellular niches for 58 persistence and replication within inflamed tissue of susceptible hosts. 59To combat intracellular bacteria, macrophages activate cell autonomous defense 60 mechanisms, such as phagocytosis, production of highly toxic reactive oxygen and nitrogen 61 species, bactericidal peptides, as well as phagosome maturation and autophagy to deliver the 62 ingested pat...