Diabetic retinopathy is a major complication of diabetes severely affecting vision. To date the disease is neither curable nor are there sufficient treatment options available that can reliably control disease progression and symptoms. Given the increasing number of diabetic patients, there is a pressing need to develop more efficient therapeutic strategies. We have previously identified that hyperglycemia causes chronic retinal tissue inflammation predominantly mediated by the activation of caspase-1 and subsequent production of interleukin-1? (IL-1?) in retinas of STZ (streptozotocin) diabetic and galactosemic mice, and in tissue of diabetic patients. M?ller cells are one of the retinal cell types that seem o be a powerful source for active caspase-1 and IL-1?. Inhibition of the caspase-1/IL-1? pathway using caspase-1 or IL-1 receptor knock out animals prevents capillary dropout and M?ller cell loss in vivo. Although the caspase-1/IL-1? pathway is crucial for the development of diabetic retinopathy, mechanisms that regulate this pathway under normal and hyperglycemic conditions have yet to be identified. Interleukin-10 (IL-10) has long been regarded as a potent anti-inflammatory cytokine with the potential to suppress IL-1? production. Surprisingly, very little is known about the role of IL-10 in diabetic retinopathy. A couple of patient based studies have correlated low levels of IL-10 with increased risk of diabetic retinopathy, whereas one study has demonstrated increased levels of IL-10 in the vitreous of diabetic patients. Preliminary data by us show that IL-10 treatment prevents hyperglycemia-induced caspase-1 activation and cell death in M?ller cells indicating that IL-10 is a potent counter-regulator of the caspase-1/IL-1beta signaling pathway. Moreover, IL-10 treatment seems to be effective in inhibiting hyperglycemia-induced caspase-1 activity several days after the hyperglycemic insult was started opening up the possibility that IL-10 treatment might be feasible as an interventional therapy. The concept of IL-10 regulating the caspase-1/IL-1beta pathway has never been explored in relation to diabetic retinopathy. This proposal will investigate the hypothesis that IL-10 counter regulates diabetes-induced activation of the caspase-1/IL-1? signaling pathway in retinal tissue.
Two Specific Aims are proposed. The role of IL-10 in the regulation of hyperglycemia-induced activation of the caspase-1/IL-1beta will be explored in vitro and in vivo using M?ller cells, STZ diabetic wild type and IL- 10-/- mice as experimental systems (Specific Aim1). In addition, the benefit of IL-10 treatment will be tested in these systems (Specific Aim 2). When completed, the project will have identified the role of IL-10 and its effectiveness in inhibiting hyperglycemia-induced caspase-1 activation and IL-1? production in vitro and vivo and will have determined whether IL-10 supplementation is a feasible strategy to inhibit diabetic retinopathy.
Diabetic retinopathy is the leading cause of blindness among young adults. The goal of this proposal is to understand the role of IL-10 in diabetic retinopathy and to develop new target directed therapies for diabetic retinopathy using IL-10 treatment.