Role of inflammation in the pathogenesis of diabetic retinopathy

Ahmed M Abu El-Asrar, Ahmed M Abu El-Asrar

Abstract

Diabetic retinopathy (DR) remains a major cause of worldwide preventable blindness. The microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, including activation of protein kinase C, increased advanced glycation end products formation, polyol pathway, and oxidative stress, and activation of the renin angiotensin system (RAS). There is an accumulating body of evidence that inflammation plays a prominent role in the pathogenesis of DR.

Keywords: Angiogenesis; diabetic retinopathy; inflammation.

Conflict of interest statement

Conflict of Interest: None declared.

References

    1. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. American Diabetes Association. Diabetic retinopathy. Diabetes Care. 2003;26:226–9.
    1. van Beijnum JR, Buurman WA, Griffioen AW. Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1) Angiogenesis. 2008;11:91–9.
    1. Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 2004;18:1450–2.
    1. Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol. 2008;30:65–84.
    1. Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2007;2007:95103.
    1. Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S. Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye. 2006;20:1366–9.
    1. Doganay S, Evereklioglu C, Er H, Türköz Y, Sevinç A, Mehmet N, et al. Comparison of serum NO, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus. Eye. 2002;16:163–70.
    1. Abu El-Asrar AM, Missotten L, Geboes K. Expression of advanced glycation end products and related molecules in diabetic fibrovascular epiretinal membranes. Clin Experiment Ophthalmol. 2010;38:57–64.
    1. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Döhmen S, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 2002;16:438–40.
    1. Makino N, Maeda T, Sugano M, Satoh S, Watanabe R, Abe N. High serum TNF-alpha level in Type 2 diabetic patients with microangiopathy is associated with eNOS down-regulation and apoptosis in endothelial cells. J Diabetes Complications. 2005;19:347–55.
    1. Ben-Mahmud BM, Mann GE, Datti A, Orlacchio A, Kohner EM, Chibber R. Tumor necrosis factor-alpha in diabetic plasma increases the activity of core 2 GlcNAc-T and adherence of human leukocytes to retinal endothelial cells: significance of core 2 GlcNAc-T in diabetic retinopathy. Diabetes. 2004;53:2968–76.
    1. Gao X, Belmadani S, Picchi A, Xu X, Potter BJ, Tewari-Singh N, et al. Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation. 2007;115:245–54.
    1. Gao X, Zhang H, Schmidt AM, Zhang C. AGE/RAGE produces endothelial dysfunction in coronary arterioles in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2008;295:H491–8.
    1. Sainson RC, Johnston DA, Chu HC, Holderfield MT, Nakatsu MN, Crampton SP, et al. TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood. 2008;111:4997–5007.
    1. Clauss M, Sunderkötter C, Sveinbjörnsson B, Hippenstiel S, Willuweit A, Marino M, et al. A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability. Blood. 2001;97:1321–9.
    1. Vincent JA, Mohr S. Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes. 2007;56:224–30.
    1. Abu El-Asrar AM, Maimone D, Morse PH, Gregory S, Reder AT. Cytokines in the vitreous of patients with proliferative diabetic retinopathy. Am J Ophthalmol. 1992;114:731–6.
    1. Abu El-Asrar AM, Van Damme J, Put W, Veckeneer M, Dralands L, Billiau A, et al. Monocyte chemotactic protein-1 in proliferative vitreoretinal disorders. Am J Ophthalmol. 1997;123:599–606.
    1. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009;116:73–9.
    1. Abu El-Asrar AM, Struyf S, Kangave D, Geboes K, Van Damme J. Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Eur Cytokine Netw. 2006;17:155–65.
    1. Maier R, Weger M, Haller-Schober EM, EL-Shabrawi Y, Wedrich A, Theisl A, et al. Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol Vis. 2008;14:637–43.
    1. Elner SG, Elner VM, Jaffe GJ, Stuart A, Kunkel SL, Strieter RM. Cytokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Curr Eye Res. 1995;14:1045–53.
    1. Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K, Ishida Y, et al. Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol. 2004;15:940–8.
    1. Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, et al. Wound healing in MIP-1alpha(-/-) and MCP-1 (-/-) mice. Am J Pathol. 2001;159:457–63.
    1. Hong KH, Ryu J, Han KH. Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood. 2005;105:1405–7.
    1. Tager AM, Kradin RL, LaCamera P, Bercury SD, Campanella GS, Leary CP, et al. Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10. Am J Respir Cell Mol Biol. 2004;31:395–404.
    1. Keane MP, Belperio JA, Arenberg DA, Burdick MD, Xu ZJ, Xue YY, et al. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999;163:5686–92.
    1. Bulter JM, Guthrie SM, Koc M, Afzal A, Caballero S, Brooks HL, et al. SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest. 2005;115:86–93.
    1. Abu El-Asrar AM, Struyf S, Verbeke H, Van Damme J, Geboes K. Circulating bone marrow-derived enedothelial precursor cells contribute to neovascularization in diabetic epiretinal membranes. Acta Ophthalmol. 2011;89:222–8.
    1. Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation. 2008;117:206–15.
    1. Reddy K, Zhou Z, Jia SF, Lee TH, Morales-Arias J, Cao Y, et al. Stromal cell-derived factor-1 stimulates vasculogenesis and enhances Ewing's sarcoma tumor growth in the absence of vascular endothelial growth factor. Int J Cancer. 2008;123:831–7.
    1. De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A, et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood. 2004;104:3472–82.
    1. Petrovic MG, Korosec P, Kosnik M, Hawlina M. Vitreous levels of interleukin-8 in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2007;143:175–6.
    1. Kuwano T, Nakao S, Yamamoto H, Tsuneyoshi M, Yamamoto T, Kuwano M, et al. Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J. 2004;18:300–10.
    1. Bagi Z, Erdei N, Papp Z, Edes I, Koller A. Up-regulation of vascular cyclooxygenase-2 in diabetes mellitus. Pharmacol Rep. 2006;58(Suppl):52–6.
    1. Abu El-Asrar AM, Missotten L, Geboes K. Expression of cyclo-oxygenase-2 and downstream enzymes in diabetic fibrovascular epiretinal membranes. Br J Ophthalmol. 2008;92:1534–9.
    1. Cook-Johnson RJ, Demasi M, Cleland LG, Gamble JR, Saint DA, James MJ. Endothelial cell COX-2 expression and activity in hypoxia. Biochim Biophys Acta. 2006;1761:1443–9.
    1. Du Y, Sarthy VP, Kern TS. Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats. Am J Physiol Regul Integr Comp Physiol. 2004;287:R735–41.
    1. Ayalasomayajula SP, Amrite AC, Kompella UB. Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur J Pharmacol. 2004;498:275–8.
    1. Tamura K, Sakurai T, Kogo H. Relationship between prostaglandin E2 and vascular endothelial growth factor (VEGF) in angiogenesis in human vascular endothelial cells. Vascul Pharmacol. 2006;44:411–6.
    1. Abu El-Asrar AM, Desmet S, Meersschaert A, Dralands L, Missotten L, Geboes K. Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus. Am J Ophthalmol. 2001;132:551–6.
    1. Abu El-Asrar AM, Meersschaert A, Dralands L, Missotten L, Geboes K. Inducible nitric oxide synthase and vascular endothelial growth factor are colocalized in the retinas of human subjects with diabetes. Eye. 2004;18:306–13.
    1. Leal EC, Manivannan A, Hosoya K, Terasaki T, Cunha-Vaz J, Ambrósio AF, et al. Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood-retinal barrier breakdown in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2007;48:5257–65.
    1. Zheng L, Du Y, Miller C, Gubitosi-Klug RA, Ball S, Berkowitz BA, et al. Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia. 2007;50:1987–96.
    1. Chan PS, Kanwar M, Kowluru RA. Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: Novel mechanism for metabolic memory. J Diabetes Complications. 2010;24:55–63.
    1. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Eriandsson-Harris H, et al. High mobility group 1B-box mediates activation of human endothelium. J Intern Med. 2003;254:375–85.
    1. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–60.
    1. Luan ZG, Zhang H, Yang PT, Ma XC, Zhang C, Guo RX. HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF- α in human umbilical vein endothelial cells. Immunobiology. 2010;215:956–62.
    1. Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, et al. Cutting edge: Extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 2006;176:12–5.
    1. Schlueter C, Weber H, Meyer B, Rogalla P, Röser K, Hauke S, et al. Angiogenetic signaling through hypoxia. HMGB1: An angiogenic switch molecule. Am J Pathol. 2005;166:1259–63.
    1. Chavakis E, Hain A, Vinci M, Carmona G, Bianchi ME, Vajkoczy P, et al. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res. 2007;100:204–12.
    1. van Beijnum JR, Dings RP, van der Linden E, Zwaans BM, Ramaekers FC, Mayo KH, et al. Gene expression of tumor angiogenesis dissected: Specific targeting of colon cancer angiogenic vasculature. Blood. 2006;108:2339–48.
    1. Hamada N, Maeyama T, Kawaguchi T, Yoshimi M, Fukumoto J, Yamada M, et al. The role of high mobility group box 1 in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008;39:440–7.
    1. Yoshizaki A, Komura K, Iwata Y, Ogawa F, Hara T, Muroi E, et al. Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: Association with disease severity. J Clin Immunol. 2009;29:180–9.
    1. Ranzato E, Patrone M, Pedrazzi M, Burlando B. Hmgb1 promotes wound healing of 3T3 mouse fibroblasts via RAGE-dependent ERK1/2 activation. Cell Biochem Biophys. 2010;57:9–17.
    1. Abu El-Asrar AM, Missotten L, Geboes K. Expression of high-mobility group box-1/ receptor for advanced glycation end products/osteopontin/early growth response-1 pathway in proliferative vitreoretinal epiretinal membranes. Mol Vis. 2011;17:508–18.
    1. El-Asrar AM, Nawaz MI, Kangave D, Geboes K, Ola MS, Ahmad S, et al. High-mobility group box-1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy. Mol Vis. 2011;17:1829–38.
    1. Giebel SJ, Menicucci G, McGuire PG, Das A. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest. 2005;85:597–607.
    1. Abu El-Asrar AM, Van den Steen PE, Al-Amro SA, Missotten L, Opdenakker G, Geboes K. Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders. Int Ophthalmol. 2007;27:11–22.
    1. Noda K, Ishida S, Inoue M, Obata K, Oguchi Y, Okada Y, et al. Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2003;44:2163–70.
    1. Jin M, Kashiwagi K, Izuka Y, Tanaka Y, Imai M, Tsukahara S. Matrix metalloproteinases in human diabetic and nondiabetic vitreous. Retina. 2001;21:28–33.
    1. Abu El-Asrar AM, Dralands L, Veckeneer M, Geboes K, Missotten L, Van Aelst I, et al. Gelatinase B in proliferative vitreoretinal disorders. Am J Ophthalmol. 1998;125:844–51.
    1. Descamps FJ, Martens E, Kangave D, Struyf S, Geboes K, Van Damme J, et al. The activated form of gelatinase B/matrix metalloproteinase-9 is associated with diabetic vitreous hemorrhage. Exp Eye Res. 2006;83:401–7.

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