TNFα Is Required for Late BRB Breakdown in Diabetic Retinopathy, and Its Inhibition Prevents Leukostasis and Protects Vessels and Neurons from Apoptosis

Abstract

Although neither TNFα nor inflammation is necessary for early BRB breakdown in DR, TNFα is critical for later complications and would be a good therapeutic target for the prevention of the progressive BRB breakdown, retinal leukostasis, and apoptosis associated with DR.

Neural inflammation and the microglial response in diabetic retinopathy

“…Recently, Huang and coworkers demonstrated that retinal leukostasis was abrogated in diabetic mice with disruption of the TNF-α gene [42]. Although diabetes did not significantly increase, and even decreased TNF-α mRNA expression in retinas of wild-type mice, lack of its expression in the knockout animals greatly reduced vascular leakage after 3 and 6 months of diabetes and neurodegeneration after 3 months of diabetes.…”

The Effect of Aluminium on the Morphologic Appearance, Viability and Phagocytic Activity of ARPE-19 Cells

“…Two mouse models of diabetes were used: streptozotocin (STZ) treatment and insulin2 gene point mutation, both of which were described in our previous reports [11].…”

“…These dose ranges were chosen based on the antibody's clinical applications. The measurements were performed at 3 or 6 months, which were the time frames used in our previous mouse knockout (KO) study [11]. The treatment cohorts were described below and illustrated in Figure 1.…”

“…The quantitative BRB assay was performed according to a previously described technique [11,20] with some modifications. Mice were sedated as above and given an IP injection of 1μCi/gram body weight of 3H-mannitol.…”

“…In PDR, TNFα protein is presented in the fibrovascular membranes of PDR [8] and increased in the vitreous fluid and plasma of patients with DR [9,10]. TNFα deficiency in mice attenuates diabetes-related retinal leukostasis, retinal cell apoptosis and breakdown of BRB [11]. TNFα inhibition by compounds inhibits the activity of caspase-3/-8, acellular capillary and vascular permeability in the rat models of diabetes [12,13].…”