title: Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization.
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.
authors: From the Cutaneous Biology Research Center, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Charlestown, Massachusetts 02129.
authors: Lizhi
authors: L
authors: He
authors: Alexander G
authors: AG
authors: Marneros
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D018793:Interleukin-13; D053583:Interleukin-1beta; D015847:Interleukin-4; D015232:Dinoprostone; D004318:Doxycycline
keywords: Angiogenesis; Antibiotics; Inflammation; Innate Immunity; Macrophages; Macular Degeneration; Wound Healing