Protective roles of the fractalkine/CX3CL1-CX3CR1 interactions in alkali-induced corneal Neovascularization through enhanced antiangiogenic factor expression
Protective roles of the fractalkine/CX3CL1-CX3CR1 interactions in alkali-induced corneal Neovascularization through enhanced antiangiogenic factor expression
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Fractalkine/CX3CL1-CX3CR1 相互作用通过增强抗血管生成因子表达对碱诱导的角膜新生血管形成的保护作用
DOI：
10.4049/jimmunol.180.6.4283
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发表时间：
2008-03-15
影响因子：
4.4
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Lu, Peirong;Li, Longbiao;Mukaida, Naofumi
巨噬细胞在角膜新生血管形成过程中积累，但其机制和作用尚不清楚。为了解决这些问题，我们在此检查了碱后角膜新生血管的形成。裂裂素受体/CX3CR1缺失小鼠的损伤，该受体通常由巨噬细胞表达。碱损伤后，CX3CR1 mRNA表达增强，角膜内f4 /80阳性巨噬细胞和gr -1阳性中性粒细胞增多。与野生型小鼠相比，cx3cri缺陷小鼠在损伤后2周的角膜新生血管形成增强，cd31阳性区域增大。同时，与野生型小鼠相比，CX3CR1缺陷小鼠中f4 /80阳性巨噬细胞的积累明显减弱，而gr -1阳性中性粒细胞的积累则不明显。损伤后，野生型和cx3cr1缺失小鼠眼内血管内皮生长因子（VEGF） mRNA表达均有相似程度的增强。然而，抗血管生成因子、血小板反应蛋白（TSP） 1、TSP-2和溶栓素和金属蛋白酶（ADAMTS） 1 mRNA的表达在野生型小鼠中比cx3cr1缺失小鼠增强得更大。双色免疫荧光分析显示f4 /80阳性细胞也表达CX3CR1和ADAMTS-1，并且在CX3CR1阳性细胞中检测到TSP-1和ADAMTS-1。CX3CL1增强了巨噬细胞中TSP-1和ADAMTS-1的表达，但不增强VEGF的表达。此外，局部应用CX3CL1抑制角膜新生血管形成2周，同时增强眼内TSP-1和ADAMTS-I的表达，但不增强VEGF。因此，这些观察结果表明，cx3cr1阳性巨噬细胞在眼内的积累可以通过产生抗血管生成因子如TSP-1和ADAMTS-1来抑制碱诱导的角膜新生血管形成，并提示使用CX3CL1治疗碱诱导的角膜新生血管的潜在疗效。
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, CX3CRI-deficient mice exhibited enhanced corneal neovascularization 2 wk after injury, as evidenced by enlarged CD31positive 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-I 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.