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Monika Jasielska, Irina Semkova, Xuan Shi, Kristina Schmidt, Dimitrios Karagiannis, Despina Kokkinou, Jerzy Mackiewicz, Norbert Kociok, Antonia M. Joussen; Differential Role of Tumor Necrosis Factor (TNF)-α Receptors in the Development of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(8):3874-3883. doi: 10.1167/iovs.09-5003.
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Tumor necrosis factor alpha (TNF)-α contributes to inflammation-associated angiogenesis. This study investigates the role of TNF-α receptors 1a and 1b in the development of choroidal neovascularization (CNV).
CNV was induced in Tnfrsf1a−/− and Tnfrsf1b−/− mice with C57Bl6/J background and their wild-type (WT) (C57Bl/6J) controls by laser damage to the Bruch's membrane. TNF-α expression in RPE/choroid was determined by Western blot analysis. Pathologic angiogenesis was estimated qualitatively and quantitatively by fluorescein angiography and histology on choroidal flat mounts and paraffin cross-sections. Inflammatory cell invasion was investigated by clodronic acid depletion of circulating macrophages and immunochemistry, and the apoptotic activity was investigated by TUNEL assay and by caspase-3 and caspase-8 expression. Receptor 1b-specific Bmx/Etk kinase was detected by immunochemistry.
TNF-α levels were elevated after laser treatment. Severe CNV lesions and increased macrophage invasion were observed in Tnfrsf1a−/− compared with WT and Tnfrsf1b−/− mice. Increased immunoreactivity for Bmx/Etk kinase corresponded to the severity of CNV formation. Reduced pathologic angiogenesis and macrophage invasion in Tnfrsf1b−/− mice (vs. WT and Tnfrsf1a−/−) was accompanied by enhanced endothelial cell apoptosis and by caspase-3 and caspase-8 activation.
Receptor 1b promotes the recruitment of inflammatory cells to the site of injury and exacerbated pathologic angiogenesis probably by way of the Bmx/Etk-kinase–dependent pathway in the absence of receptor 1a. On the other hand, receptor 1a–dependent apoptosis in the absence of receptor 1b leads to reduced inflammatory response and CNV lesions after laser treatment. This demonstrates the potential for specific targeting of TNF-α receptors for future therapies of inflammation-associated choroidal neovascularization.
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