Abstract
Pathological choroidal neovascularization (CNV) is the common cause of vision loss in patients with age-related macular degeneration (AMD). Macrophages possess potential angiogenic function in CNV. We have demonstrated that human T lymphocyte-derived microparticles (LMPs) exert a potent antiangiogenic effect in several pathological neovascularization models. In this study, we investigated the alteration of proangiogenic properties of macrophages by LMPs treatment in vitro and in vivo models. LMPs regulated the expression of several angiogenesis-related factors in macrophages and consequently stimulated their antiangiogenic effects evidenced by the suppression of the proliferation of human retinal endothelial cells in co-culture experiments. The involvement of CD36 receptor in LMPs uptake by macrophages was demonstrated by in vitro assays and by immunostaining of choroidal flat mounts. In addition, ex vivo experiments showed that CD36 mediates the antiangiogenic effect of LMPs in murine and human choroidal explants. Furthermore, intravitreal injection of LMPs in the mouse model of laser-induced CNV significantly suppressed CNV in CD36 dependent manner. The results of this study suggested an ability of LMPs to alter the gene expression pattern of angiogenesis-related factors in macrophages, which provide important information for a new therapeutic approach for efficiently interfering with both vascular and extravascular components of CNV.
Highlights
Lymphocyte-derived microparticles (LMPs) are small membrane microvesicles released from human T lymphocytes during apoptosis[1,2]
Given the important role of CD36 in macrophages, we investigated whether LMPs modulate the angiogenic microenvironment by altering macrophage phenotype, and whether CD36 is involved in the LMPs-induced antiangiogenic effects
Similar effects of LMPs were observed on bone marrow-derived macrophages (BMDM) from femurs of C57BL/6 mice and on human macrophages differentiated from HL60 cells (Supplementary Figures S1 and S2)
Summary
Lymphocyte-derived microparticles (LMPs) are small membrane microvesicles released from human T lymphocytes during apoptosis[1,2]. LMPs suppress microvessel sprouting in aortic ring[3] and choroidal explants[6] These effects depended upon on the integrity of the retinal pigment epithelium (RPE) and involved release of pigment epithelium-derived growth factor (PEDF) and p75 neurotrophin receptor (p75NTR)[6]. Activation of the interferon-βsignaling pathway in retinal macrophages and microglia cells reduces the inflammation and limits the development of CNV lesions[12]. These data suggest that modulation of macrophages and microglia activity may become an attractive therapeutic tool for the treatment of neovascular AMD. Given the important role of CD36 in macrophages, we investigated whether LMPs modulate the angiogenic microenvironment by altering macrophage phenotype, and whether CD36 is involved in the LMPs-induced antiangiogenic effects
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