Fine-tuning of macrophage activation using synthetic rocaglate derivatives

Sci Rep. 2016 Apr 18:6:24409. doi: 10.1038/srep24409.

Abstract

Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Cell Line
  • Drug Synergism
  • Francisella tularensis / drug effects
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon Type I / antagonists & inhibitors
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Macrophage Activation / drug effects*
  • Macrophages / drug effects*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Pilot Projects
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • Irf1 protein, mouse
  • Interferon-gamma
  • Nitric Oxide Synthase Type II