title: CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization.
abstract: Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMΦ) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1β when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE2-conditioned CD200R(-/-) BMMΦ, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMΦ angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development.
authors.affiliation: 1] Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, UK [2] Department of Ophthalmology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan [3].
authors.forename: Shintaro
authors.initials: S
authors.lastname: Horie
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Robbie
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Wei-Kang
authors.initials: WK
authors.lastname: Wu
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Nicholson
authors.forename: Manabu
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C492346:CD200 receptor, mouse; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D015232:Dinoprostone