A Role for Systemic Inflammation in Diabetic Retinopathy

Introduction

Diabetic retinopathy is a sight-threatening microvascular complication of diabetes. Several hypotheses have been offered to explain the vascular pathology caused by diabetes, but a role for adhesion of leukocytes to the retinal vasculature (leukostasis) is broadly accepted as a contributing factor. Understanding the processes that lead to leukostasis may therefore foster new preventive treatments. In diabetic animals, leukostasis is promoted by enhanced expression of adhesion molecules on the retinal endothelium and the expression of integrins on circulating leukocytes. Knockout mice, lacking intracellular adhesion molecule (ICAM-1) or leukocyte integrin CD18, each exhibited reduced retinal capillary damage and vascular permeability during diabetes. ¹ Tumor necrosis factor alpha (TNF-α) may play a role in this process, as deletion of the TNF-α gene abrogated leukostasis, retinal cell death, and vascular permeability in diabetic mice. ²  

Arita and colleagues ³ found that levels of TNF-α and soluble TNF receptors, an indication of ongoing TNF-α signaling, were increased in sera of DR patients and correlated with disease severity. Moreover, TNF-α in sera from advanced DR patients activated endothelial cells in culture, increasing downstream Rho kinase (ROCK) activity leading to expression of ICAM-1. TNF-α and ROCK activation also triggered translocation of CD18 and CD11b integrins to the surface of neutrophils, which allows binding to ICAM-1. ⁴ These data suggest that elevated systemic TNF-α may increase both adhesiveness of retinal endothelium and capacity of leukocytes to adhere. The results further suggest that processes leading to leukostasis may not originate in the retina, but rather are the result of low but persistent systemic inflammation caused by diabetes. 

Indeed, a recent clinical study of 11 patients with severe retinopathy refractory to conventional therapy found that systemic administration of a TNF-α blocking antibody (infliximab) produced a significant 24% increase in visual acuity. ⁵ Collectively, these studies build the case for systemic inflammation and TNF-α as potential therapeutic targets for DR.