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Critical Role of TNF-α-Induced Macrophage VEGF and iNOS Production in the Experimental Corneal Neovascularization

2012; Cadmus Press; Volume: 53; Issue: 7 Linguagem: Inglês

10.1167/iovs.10-5548

1552-5783

Peirong Lu, Longbiao Li, Gaoqin Liu, Tomohisa Baba, Yuko Ishida, Mizuho Nosaka, Toshikazu Kondo, Xueguang Zhang, Naofumi Mukaida,

Ocular Surface and Contact Lens

We evaluated the roles of tumor necrosis factor (TNF)-α in alkali-induced corneal neovascularization (CNV).CNV was induced by alkali injury and compared in wild-type (WT) BALB/c mice, and TNF receptor 1-deficient (TNF-Rp55 KO) counterparts, or in mice treated with TNF-α antagonist and recombinant TNF-α. Angiogenic factor expression and leukocyte accumulation in the early phase after injury were quantified by real-time PCR and immunohistochemical analysis, respectively.Alkali injury augmented the intraocular mRNA expression of TNF-α and its receptor, together with a transient macrophage and neutrophil infiltration. Compared to WT mice, TNF-Rp55 KO mice exhibited reduced CNV. Intraocular F4/80-positive macrophages and Ly-6G-positive neutrophils infiltration did not change in KO mice compared to WT mice after the injury. Alkali injury induced a massively increased intraocular mRNA expression of angiogenic factors, including vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), interleukin (IL)-6, E-selectin, and intercellular adhesion molecule (ICAM)-1 in WT mice, whereas these increments were retarded severely in KO mice. Immunofluorescence analysis demonstrated that F4/80-positive cells expressed VEGF and iNOS. Moreover, TNF-α enhanced VEGF and iNOS expression by peritoneal macrophage from WT, but not KO mice. Topical application of TNF-α antagonist reduced CNV, while topical application of recombinant TNF-α enhanced it.TNF-Rp55-KO mice exhibited impaired alkali-induced CNV through reduced intracorneal infiltrating macrophage VEGF and iNOS expression.