TNF is Essential for Progressive BRB Breakdown in Diabetic Retinopathy and Oxygen-Induced Ischemic Retinopathy and It Promotes Apoptosis in Retinal Vessels and Neurons

Abstract

Purpose: : Blood-retinal barrier (BRB) breakdown in diabetic retinopathy (DR) and other ocular disorders is associated with inflammation and retinal leukostasis is almost totally suppressed in the absence of TNFα. This study was conducted to determine whether TNFα is critical for BRB breakdown in DR and other ischemic retinopathies and for apoptosis of retinal vascular cells and neurons resulting from oxidative stress and in DR.

Methods: : Diabetes was induced in TNFα(KO) mice with streptozotocin (STZ). Ins2^Akita mice were crossed with TNFα(KO) mice to provide a genetic model of diabetes, devoid of TNFα. Oxygen-induced ischemic retinopathy (OIR) was induced by placing P7 mice in 75% oxygen for 5 days and removing them to room air for 5 days. The BRB was assessed using a quantitative assay with ³H-mannitol as a tracer. Apoptosis was evaluated with TUNEL and activated caspase-3 staining.

Results: : The absence of TNFα did not influence DR-associated BRB breakdown at 6 weeks, but it completely prevented it at 3 months in TNFα(KO) X Ins2^Akita mice and at 6 months in STZ-diabetic TNFα(KO) mice and it significantly reduced BRB breakdown in OIR. An absence of TNFα also significantly reduced apoptosis after 3 months of STZ-induced diabetes and protected retinal vascular cells in the inner and outer plexiform layers, photoreceptors, retinal ganglion cells, and retinal neurons in the inner nuclear layer from oxidative stress-induced apoptosis, which is associated with age-related macular degeneration (AMD).

Conclusions: : TNFα is critical for late, but not early BRB breakdown in DR and it promotes BRB breakdown in OIR. This suggests that TNFα-induced inflammation is not responsible for the early BRB breakdown that occurs in DR, but it may be essential for the later BRB breakdown and apoptosis in the retina as the disease progresses. TNFα blockade also protects retinal vascular cells and neurons from oxidative stress. The results suggest that TNFα inhibition could provide benefit in DR and other ischemic retinopathies as well as in AMD.

Keywords: diabetic retinopathy • age-related macular degeneration • apoptosis/cell death