Role of 4 Integrin (CD49d) in the Pathogenesis of Diabetic Retinopathy

Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 07/2009; 50(10):4898-904. DOI: 10.1167/iovs.08-2013
Source: PubMed


The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin alpha 4/CD49d in the pathogenesis of diabetic retinopathy.
Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-alpha 4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF-alpha levels and NF-kappaB activity were measured by ELISA.
Blockade of alpha 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-kappaB activation, VEGF, and TNF-alpha protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage.
These data identify alpha 4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.

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    • "Integrins are also among various factors that cause retinal detachment in proliferative diabetic retinopathy and proliferative vitreoretinopathy (Kupper and Ferguson 1993; Guidry et al. 2003). In rats, blockade of α4 integrin diminished diabetes-induced increase in NF-kappaB activation , VEGF and TNF-alpha levels and significantly reduced leukocyte adhesion and vascular leakage (Iliaki et al. 2009). Synthetic peptide antagonists of integrin αvβ3 inhibited retinal neovascularization in a murine model when administered as intraperitonal or periocular injections (Luna et al. 1996), inhibition of αv integrins prevented basic fibroblast growth factor-induced neovascularization of cornea (Klotz et al. 2000), and inhibition of α5β1 inhibited and regressed corneal neovascularization after alkali-burns (Muether et al. 2007). "
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    ABSTRACT: Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.
    Full-text · Article · Mar 2014 · Journal of Cell Communication and Signaling
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    • "Previously, CD29/integrin β1 [52], CD51/integrin αV, and CD44/HCAM have been described to be present on the surface of hRPE cells [45, 53, 54], but we detected more positivity for integrin α1 and integrin α2 in our primary hRPE cell cultures compared to the studies published to date [53]. Our fvERM cells expressed low levels of the α-subunit-containing integrins, besides a reported expression of integrin α4 in diabetic retinopathy [53, 55]. Interestingly, the presence of integrin β2 subunit has been considered important factor in the RPE-T cell interaction [56]. "
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    ABSTRACT: Characterization of the cell surface marker phenotype of ex vivo cultured cells growing out of human fibrovascular epiretinal membranes (fvERMs) from proliferative diabetic retinopathy (PDR) can give insight into their function in immunity, angiogenesis, and retinal detachment. FvERMs from uneventful vitrectomies due to PDR were cultured adherently ex vivo. Surface marker analysis, release of immunity- and angiogenesis-pathway-related factors upon TNF α activation and measurement of the intracellular calcium dynamics upon mechano-stimulation using fluorescent dye Fura-2 were all performed. FvERMs formed proliferating cell monolayers when cultured ex vivo, which were negative for endothelial cell markers (CD31, VEGFR2), partially positive for hematopoietic- (CD34, CD47) and mesenchymal stem cell markers (CD73, CD90/Thy-1, and PDGFR β ), and negative for CD105. CD146/MCAM and CD166/ALCAM, previously unreported in cells from fvERMs, were also expressed. Secretion of 11 angiogenesis-related factors (DPPIV/CD26, EG-VEGF/PK1, ET-1, IGFBP-2 and 3, IL-8/CXCL8, MCP-1/CCL2, MMP-9, PTX3/TSG-14, Serpin E1/PAI-1, Serpin F1/PEDF, TIMP-1, and TSP-1) were detected upon TNF α activation of fvERM cells. Mechano-stimulation of these cells induced intracellular calcium propagation representing functional viability and role of these cells in tractional retinal detachment, thus serving as a model for studying tractional forces present in fvERMs in PDR ex vivo.
    Full-text · Article · Aug 2013
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    • "Increased leukocyte adhesion (via ICAM1-CD18) to retinal vascular endothelium with resulting endothelial damage, breakdown of the blood retina barrier, capillary nonperfusion, and ischemia contribute to neovascularization. Inhibition of integrin α-4, which forms a part of very late antigen-4 (VLA-4) that binds to VCAM-1, decreases TNF-α, VEGF, NF-κB and reduces leukocyte adhesion and vascular leakage [95]. Cytokines produced by inflammatory cells play a central role in the pathogenesis of PDR by promoting leucocyte-mediated damage to retinal vasculature [96]. "
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    ABSTRACT: The causes of retinal hypoxia are many and varied. Under hypoxic conditions, a variety of soluble factors are secreted into the vitreous cavity including growth factors, cytokines, and chemokines. Cytokines, which usually serve as signals between neighboring cells, are involved in essentially every important biological process, including cell proliferation, inflammation, immunity, migration, fibrosis, tissue repair, and angiogenesis. Cytokines and chemokines are multifunctional mediators that can direct the recruitment of leukocytes to sites of inflammation, promote the process, enhance immune responses, and promote stem cell survival, development, and homeostasis. The modern particle-based flow cytometric analysis is more direct, stable and sensitive than the colorimetric readout of the conventional ELISA but, similar to ELISA, is influenced by vitreous hemorrhage, disruption of the blood-retina barrier, and high serum levels of a specific protein. Finding patterns in the expression of inflammatory cytokines specific to a particular disease can substantially contribute to the understanding of its basic mechanism and to the development of a targeted therapy.
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