Differential Role of Tumor Necrosis Factor (TNF)-α Receptors in the Development of Choroidal Neovascularization

Jasielska, Monika; Semkova, Irina; Shi, Xuan; Schmidt, Kristina; Karagiannis, Dimitrios; Kokkinou, D.; Mackiewicz, Jerzy; Kociok, Norbert; Joussen, Antonia M.

doi:10.1167/iovs.09-5003

Cited by 42 publications

(40 citation statements)

References 26 publications

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“…Compared with unlasered controls, TNF-a staining was greater in the overlying retina of laser-treated eyes and also colocalized with isolectinlabeled CECs within CNV ( Figure 1B). Similar to previous reports, 7,8 laser-induced CNV volume was significantly reduced in mice treated with intravitreal neutralizing Ab to mouse TNF-a (TNF-a Ab) compared with mice treated with intravitreal isotype IgG control (Figure 1, C and D).…”

Section: Up-regulation Of Tnf-a Is Associated With the Development Ofsupporting

confidence: 90%

“…5 The inflammatory cytokine, tumor necrosis factor (TNF)-a, was found in macrophages within CNV surgically removed from patients with neovascular AMD. 6 Inhibition of TNF-a bioactivity by neutralizing antibodies 7 or by targeting TNF-a receptor 1 8 reduced the volume and leakage of laser-induced CNV in experimental models, suggesting that TNF-aemediated signaling was important in the development of CNV. 9,10 The roles of TNF-aemediated inflammation in rheumatoid arthritis, Alzheimer disease, atherosclerosis, and diabetes have been well established, 11 and activation of NF-kB by TNF-a plays a fundamental role in these chronic inflammatory diseases.…”

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confidence: 99%

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Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Wang

Fotheringham

Wittchen

et al. 2015

The American Journal of Pathology

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Macrophage-derived tumor necrosis factor (TNF)-a has been found in choroidal neovascularization (CNV) surgically removed from patients with age-related macular degeneration. However, the role of TNF-a in CNV development remains unclear. In a murine laser-induced CNV model, compared with un-lasered controls, TNF-a mRNA was increased in retinal pigment epithelial and choroidal tissue, and TNF-a colocalized with lectin-stained migrating choroidal endothelial cells (CECs). Inhibition of TNF-a with a neutralizing antibody reduced CNV volume and reactive oxygen species (ROS) level around CNV. In CECs, pretreatment with the antioxidant apocynin or knockdown of p22phox, a subunit of NADPH oxidase, inhibited TNF-aeinduced ROS generation. Apocynin reduced TNF-aeinduced NF-kB and Rac1 activation, and inhibited TNF-aeinduced CEC migration. TNF-aeinduced Rac1 activation and CEC migration were inhibited by NF-kB inhibitor Bay11-7082. Overexpression of Rap1a prevented TNF-aeinduced ROS generation and reduced NF-kB and Rac1 activation. Activation of Rap1 by 8-(4-chlorophenylthio) adenosine-2 0 -O-Me-cAMP prevented TNF-aeinduced CEC migration and reduced laser-induced CNV volume, ROS generation, and activation of NF-kB and Rac1. These findings provide evidence that active Rap1a inhibits TNF-aeinduced CEC migration by inhibiting NADPH oxidase-dependent NF-kB and Rac1 activation and suggests that Rap1a de-escalates CNV development by interfering with ROSdependent signaling in several steps of the pathogenic process. One reason may be that treatment is provided too late when CNV is already present. To address this possibility, we focus on understanding early steps in the pathophysiology in neovascular AMD to prevent vision loss. Activation and migration of choroidal endothelial cells (CECs) are early steps in the development of CNV. Activated CECs migrate through the Bruch membrane toward the retinal pigment epithelium (RPE) and also transmigrate the RPE into the sensory retina. At either location, activated CECs can proliferate to form CNV. Severe vision loss occurs when CNV develops in the sensory retina. 3,4 Both inflammation and oxidative stress have been implicated in the development of CNV.

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Section: Up-regulation Of Tnf-a Is Associated With the Development Ofsupporting

confidence: 90%

mentioning

confidence: 99%

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Wang

Fotheringham

Wittchen

et al. 2015

The American Journal of Pathology

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“…[29][30][31] dative stress was found to activate the canonical Wnt pathway in the retinas of oxygen-induced retinopahty rats. 32 Moreover, inflammation pathways have potent cross-talks with the Wnt signaling pathway, 33 and our previous study showed that inflammation factors such as TNF-a and ICAM-1 are upregulated in the rat retina after activation of the Wnt pathway. 24 Our results demonstrate that levels of LRP6, phosphorylated LRP6, and b-catenin are significantly elevated in the eyecups of the laser-induced CNV rodent models, demonstrating activation of Wnt signaling.…”

Section: Discussionmentioning

confidence: 97%

Pathogenic Role of the Wnt Signaling Pathway Activation In Laser-Induced Choroidal Neovascularization

Chen

Lin

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Choroidal neovascularization (CNV) is a severe complication of AMD. The Wnt signaling pathway has been shown to mediate angiogenesis. The purpose of this study was to investigate the pathogenic role of the Wnt pathway in CNV and explore the therapeutic potential of a novel Wnt signaling inhibitor in CNV.METHODS. Adult rats and mice were photocoagulated using diode laser to induce CNV. On the same day, the animals were intravitreally injected with a monoclonal antibody (Mab2F1) blocking LRP6 or nonspecific mouse IgG. The Wnt signaling activation and target gene expression in the eyecup were determined by Western blot analysis. Fundus angiography was used to examine leakage from the laser lesion. CNV areas were measured on choroidal flatmount using FITC-dextran. The canonical wingless-type MMTV integration site (Wnt) signaling pathway plays a critical role in the regulation of inflammation and angiogenesis. 5,6 Wnt ligands are secreted, cysteine-rich glycosylated proteins, 3 which bind to frizzled (Fz) receptors or to the coreceptor complex of Fz and low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6). RESULTS. Levels of 4-6Binding of Wnt ligands results in LRP6 phosphorylation and activation, 7,8 leading to dissociation of the kinase complex containing glycogen synthase kinase-3b (GSK3b), 9 axin and adenomatous polyposis.3 The GSK3b complex dissociation prevents transcription factor b-catenin from phosphorylation and degradation.10 Consequently, b-catenin is accumulated in the cytoplasm and translocated into the nucleus, complexes with TCF/LEF family transcription factors, 11 regulating expression of Wnt target genes including VEGF, which is the key pathogenic factor in CNV. [12][13][14][15] Although studies of the pathogenesis and treatment of AMD have been delayed by lacking of ideal animal models, 16 laserinduced CNV rodent models are commonly used to study CNV in wet AMD. [17][18][19][20] Moreover, our previous study has shown that the Wnt signaling pathway is activated in very low-density lipoprotein receptor (VLDLR) knockout (KO) mice, a genetic animal model of subretinal neovascularization (NV). 21 The present study investigated the role of the Wnt signaling pathway in laser-induced CNV and explored therapeutic potential of a blocker of Wnt signaling in laser-induced CNV and VLDLR KO models. METHODS AnimalsCare, use, and treatment of experimental animals were in strict agreement with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male C57BL/6J mice and VLDLR KO mice (10 weeks old; The Jackson Laboratory, Bar Harbor, ME) and male Brown Norway rats (8-10 weeks old; Charles River, Wilmington, MA) were used in this study. In all procedures, animals were anesthetized by intramuscular injection of 50 mg/kg ketamine hydrochloride (Vedco, St. Joseph, MO) and 10 mg/kg xylazine (Vedco), and pupils were dilated with topical administration of 1% cyclopentolate (Wilson, Mustang, OK). CNV InductionLaser photocoagulation (532 nm, 150-250 mW, 0.01 second, 50 lm; model di...

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“…TNF-a, A PROINFLAMMATORY cytokine, is highly expressed in ischemic tissue (1)(2)(3)(4)(5) and plays a critical role in ischemiainduced recovery and regeneration processes in skeletal muscle and heart tissues (6)(7)(8)(9)(10)(11)(12). TNF-a mediates activation of divergent intracellular signaling pathways through 2 of its receptors, TNFR1 (p55) and TNFR2 (p75) (13)(14)(15)(16).…”

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confidence: 99%

Genetic deletion of TNFR2 augments inflammatory response and blunts satellite‐cell‐mediated recovery response in a hind limb ischemia model

et al. 2014

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We have previously shown that TNF-tumor necrosis factor receptor-2/p75 (TNFR2/p75) signaling plays a critical role in ischemia-induced neovascularization in skeletal muscle and heart tissues. To determine the role of TNF-TNFR2/p75 signaling in ischemia-induced inflammation and muscle regeneration, we subjected wildtype (WT) and TNFR2/p75 knockout (p75KO) mice to hind limb ischemia (HLI) surgery. Ischemia induced significant and long-lasting inflammation associated with considerable decrease in satellite-cell activation in p75KO muscle tissue up to 10 d after HLI surgery. To determine the possible additive negative roles of tissue aging and the absence of TNFR2/p75, either in the tissue or in the bone marrow (BM), we generated 2 chimeric BM transplantation (BMT) models where both young green fluorescent protein (GFP)-positive p75KO and WT BM-derived cells were transplanted into adult p75KO mice. HLI surgery was performed 1 mo after BMT, after confirming complete engraftment of the recipient BM with GFP donor cells. In adult p75KO with the WT-BMT, proliferative (Ki67 + ) cells were detected only by d 28 and were exclusively GFP + , suggesting significantly delayed contribution of young WT-BM cell to adult p75KO ischemic tissue recovery. No GFP + young p75KO BM cells survived in adult p75KO tissue, signifying the additive negative roles of tissue aging combined with decreased/absent TNFR2/p75 signaling in postischemic recovery.-Sasi, S. P., Rahimi, L., Yan, X., Silver, M., Qin, G., Losordo, D. W., Kishore, R., Goukassian, D. A. Genetic deletion of TNFR2 augments inflammatory response and blunts satellite-cell-mediated recovery response in a hind limb ischemia model. FASEB J. 29, 1208-1219 (2015). www.fasebj.org

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Differential Role of Tumor Necrosis Factor (TNF)-α Receptors in the Development of Choroidal Neovascularization

Cited by 42 publications

References 26 publications

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Rap1 GTPase Inhibits Tumor Necrosis Factor-α–Induced Choroidal Endothelial Migration via NADPH Oxidase– and NF-κB–Dependent Activation of Rac1

Pathogenic Role of the Wnt Signaling Pathway Activation In Laser-Induced Choroidal Neovascularization

Genetic deletion of TNFR2 augments inflammatory response and blunts satellite‐cell‐mediated recovery response in a hind limb ischemia model

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