Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization

J Biol Chem. 2014 Mar 21;289(12):8019-28. doi: 10.1074/jbc.M113.535765. Epub 2014 Feb 6.

Abstract

Macrophages occur along a continuum of functional states between M1-type polarized macrophages with antiangiogenic and antitumor activity and M2-type polarized macrophages, which have been implicated to promote angiogenesis and tumor growth. Proangiogenic M2-type macrophages promote various pathologic conditions, including choroidal neovascularization in models of neovascular age-related macular degeneration, or certain cancers, such as glioblastoma multiforme. Thus, a potential novel therapeutic approach to target pathological angiogenesis in these conditions would be to inhibit the polarization of macrophages toward the proangiogenic M2-type. However, no pharmacological inhibitors of M2-type macrophage polarization have been identified yet. Here we performed an unbiased pharmacological and small chemical screen to identify drugs that inhibit proangiogenic M2-type macrophage polarization and block pathologic macrophage-driven neovascularization. We identified the well tolerated and commonly used antibiotic doxycycline as a potent inhibitor of M2-type polarization of macrophages. Doxycycline inhibited, in a dose-dependent manner, M2-type polarization of human and bone marrow-derived mouse macrophages without affecting cell viability. Furthermore, doxycycline inhibited M2-type macrophage polarization and subsequent neovascularization in vivo in a laser injury model of choroidal neovascularization. Thus, doxycycline could be used to enhance current antiangiogenic treatment approaches in various conditions that are promoted by proangiogenic M2-type macrophages, including neovascular age-related macular degeneration and certain cancers.

Keywords: Angiogenesis; Antibiotics; Inflammation; Innate Immunity; Macrophages; Macular Degeneration; Wound Healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Cell Line
  • Cell Survival / drug effects
  • Cells, Cultured
  • Choroidal Neovascularization / drug therapy*
  • Choroidal Neovascularization / pathology
  • Dinoprostone / immunology
  • Doxycycline / pharmacology
  • Doxycycline / therapeutic use*
  • Female
  • Humans
  • Interleukin-13 / immunology
  • Interleukin-1beta / immunology
  • Interleukin-4 / immunology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Angiogenesis Inhibitors
  • Anti-Bacterial Agents
  • Interleukin-13
  • Interleukin-1beta
  • Interleukin-4
  • Dinoprostone
  • Doxycycline