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* Clinical Immunology Key Laboratory of Jiangsu Province and
Department of Ophthalmology, First Affiliated Hospital of Suzhou University, Suzhou, China; and
Division of Molecular Bioregulation and
Division of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
Macrophages accumulate during the course of corneal neovascularization, but its mechanisms and roles still remain elusive. To address these points, we herein examined corneal neovascularization after alkali injury in mice deficient in fractalkine receptor/CX3CR1, which is normally expressed by macrophages. After alkali injury, the mRNA expression of CX3CR1 was augmented along with accumulation of F4/80-positive macrophages and Gr-1-positive neutrophils in the corneas. Compared with wild-type mice, CX3CR1-deficient mice exhibited enhanced corneal neovascularization 2 wk after injury, as evidenced by enlarged CD31-positive areas. Concomitantly, the accumulation of F4/80-positive macrophages, but not Gr-1-positive neutrophils, was markedly attenuated in CX3CR1-deficient mice compared with wild-type mice. The intraocular mRNA expression of vascular endothelial growth factor (VEGF) was enhanced to similar extents in wild-type and CX3CR1-deifient mice after the injury. However, the mRNA expression of antiangiogenic factors, thrombospondin (TSP) 1, TSP-2, and a disintegrin and metalloprotease with thrombospondin (ADAMTS) 1, was enhanced to a greater extent in wild-type than CX3CR1-deificient mice. A double-color immunofluorescence analysis demonstrated that F4/80-positive cells also expressed CX3CR1 and ADAMTS-1 and that TSP-1 and ADAMTS-1 were detected in CX3CR1-positive cells. CX3CL1 enhanced TSP-1 and ADAMTS-1, but not VEGF, expression by peritoneal macrophages. Moreover, topical application of CX3CL1 inhibited corneal neovascularization at 2 wk, along with enhanced intraocular expression of TSP-1 and ADAMTS-1 but not VEGF. Thus, these observations indicate that accumulation of CX3CR1-positive macrophages intraocularly can dampen alkali-induced corneal neovascularization by producing antiangiogenic factors such as TSP-1 and ADAMTS-1 and suggest the potential therapeutic efficacy of using CX3CL1 against alkali-induced corneal neovascularization.
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1 This work was supported by the International Cooperative Program of Kanazawa University (to N.M.) and the National Natural Science Foundation in China (Grants 30572120 and 30771978), the Jiangsu Natural Science Foundation (Grant BK2006528), the China Postdoctoral Science Foundation (Grant 2005038587), grants from the Suzhou University (to P.L.), and the National Natural Science Key Program Foundation in China (Grant 30330540 to X.Z.).
2 Address correspondence and reprint requests to Dr. Naofumi Mukaida, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. E-mail address: naofumim{at}kenroku.kanazawa-u.ac.jp or Dr. Xueguang Zhang, Clinical Immunology Key Laboratory of Jiangsu Province, Suzhou University, 188 Shizi Street, Suzhou 215006, China. E-mail address: smbxuegz{at}public1.sz.js.cn
3 Abbreviations used in this paper: CNV, corneal neovascularization; ADAMTS, a disintegrin and metalloprotease with thrombospondin; pAb, polyclonal Ab; VEGF, vascular endothelial growth factor; TSP, thrombospondin; WT, wild type; CT, threshold cycle; AMD, age-related macular degeneration.
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