Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis
Sujoy Chatterjee,
Shivraj M. Yabaji,
Oleksii S. Rukhlenko,
Bidisha Bhattacharya,
Emily Waligurski,
Nandini Vallavoju,
Somak Ray,
Boris N. Kholodenko,
Lauren E. Brown,
Aaron B. Beeler,
Alexander R. Ivanov,
Lester Kobzik,
John A. Porco, Jr.,
Igor Kramnik
Affiliations
Sujoy Chatterjee
Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA
Shivraj M. Yabaji
Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA
Oleksii S. Rukhlenko
Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland
Bidisha Bhattacharya
Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA
Emily Waligurski
Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA
Nandini Vallavoju
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
Somak Ray
Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
Boris N. Kholodenko
Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; Department of Pharmacology, Yale University School of Medicine, New Haven, USA
Lauren E. Brown
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
Aaron B. Beeler
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
Alexander R. Ivanov
Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
Lester Kobzik
Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
John A. Porco, Jr.
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
Igor Kramnik
Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA; Corresponding author
Summary: Macrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors. We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatment of primary macrophages with rocaglates enhanced phagosome-lysosome fusion and control of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization toward the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., chronic bacterial infections, allergies, and, possibly, certain tumors.
