Inflammation in diabetic retinopathy

Abstract

Diabetes causes a number of metabolic and physiologic abnormalities in the retina, but which of these abnormalities contribute to recognized features of diabetic retinopathy (DR) is less clear. Many of the molecular and physiologic abnormalities that have been found to develop in the retina in diabetes are consistent with inflammation. Moreover, a number of anti-inflammatory therapies have been found to significantly inhibit development of different aspects of DR in animal models. Herein, we review the inflammatory mediators and their relationship to early and late DR, and discuss the potential of anti-inflammatory approaches to inhibit development of different stages of the retinopathy. We focus primarily on information derived from in vivo studies, supplementing with information from in vitro studies were important.

Fig 1

A. Fundus image of a patient with moderate nonproliferative diabetic retinopathy (NPDR). Microaneurysms can be seen (black arrows) along with an area containing a flame-hemorrhage (yellow arrowhead) and exudates (white arrow) temporal to the fovea. B. Fundus image of a patient with proliferative diabetic retinopathy (PDR). Multiple areas containing microaneurysms can be seen here (black arrows) along with an area of neovascularization of the optic disc (yellow arrowhead) and exudates (white arrow) superotemporal to the fovea. C. Fluorescein angiogram of patient seen in B. Areas of profound retinal nonperfusion are identified by a star. Numerous white dots (white arrows) indicate the presence of microaneurysms, which are more easily visualized on fluorescein angiograms than color photos. D. Isolated retinal microvessels from a diabetic patient demonstrating numerous capillary microaneurysms (thick arrows) and degenerate capillaries (thin arrows).

Fig 2

Summary of the relation of the innate immune system to inflammation. As indicated in the text, many of the components of this system are found to be abnormal in retinas of diabetic animals. 1l-1R1, interleukin-1 receptor; AGEs, advanced glycation endproducts; HMGB1, high mobility box group 1; TNFαR, receptor for TNFα; MyD88, Myeloid differentiation primary response gene (88); IRAK, Interleukin-1 receptor-associated kinases; IKK, IκB kinase; p38; p38 MAP kinase

Fig 3

Genetic deletion of the proinflammatory protein, iNOS, inhibits diabetes-induced (a) capillary degeneration and (b) pericyte loss in retinal vessels from mice diabetic for 9 months. N, nondiabetic; SD, streptozotocin diabetic; WT, wildtype; iNOS^-/-, iNOS deficient. (Used with kind permission from Springer Science+Business Media: Diabetologia. Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. 2007 50(9):1987-96; Zheng L, Du Y, Miller C, Gubitosi-Klug RA, Ball S, Berkowitz BA, Kern TS; Fig 4).

Fig 4

A. Deletion of either 5- or 12 lipoxygenase significantly inhibited diabetes-induced leukostasis compared to nondiabetic controls. Wildtype mice and mice genetically deficient in 5-lipoxygenase or 12-lipoxygensase were made diabetic for 9 months or kept as nondiabetic controls. B. Inhibition of diabetes-induced capillary degeneration by deficiency of 5-lipoxygenase, but not 12-lipoxygenase. N, nondiabetic; D, diabetic. (Copyright 2008 American Diabetes Association From Diabetes, Vol. 57, 2009; 1387-1393 Reprinted with permission from the American Diabetes Association).

Fig 5

Schematic summarizing transcellular transfer between the retina and marrow-derived cells that is postulated to contribute to inflammatory changes and cell death in diabetic retinopathy.

Fig 6

Adherence of a leukocyte to the wall of a retinal capillary (leukostasis). The vasculature has been perfused to remove all free blood cells and plasma, and then the vasculature perfused with Concanavalin A-FITC, which stains the endothelium light green, and adherent leukocytes bright green (arrow).

Fig 7

Postulated scheme by which inflammation contributes to retinal capillary degeneration in diabetes. The scheme shows a series of steps which were elucidated by inhibiting a specific protein (such as iNOS), and then determining which other steps (or proteins) also were inhibited (and thus were regulated by that protein). RAGE also fits into this scheme, but its position relative to many of these other abnormalities is not yet clear.