期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 12, 页码 8019-8028出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.535765
关键词
Angiogenesis; Antibiotics; Inflammation; Innate Immunity; Macrophages; Wound Healing; Macular Degeneration
资金
- NEI, National Institutes of Health [NEI R01-EY019297]
- Shiseido research grant
- Dermatology Foundation
Background: M2-type macrophages are proangiogenic and protumorigenic, whereas M1-type macrophages are antiangiogenic. Results: Doxycycline is a potent inhibitor of M2-type macrophage polarization in both human and mouse macrophages in vitro and in vivo. Conclusion: Preventing M2-type macrophage polarization correlates with inhibition of pathological angiogenesis. Significance: Doxycycline may be used to enhance current antiangiogenic treatment approaches in neovascular age-related macular degeneration and in certain cancers. 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.
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