Abstract
Diabetic retinopathy is the leading cause of blindness in the working-age population worldwide. Although the cause of diabetic retinopathy is multifactorial, IL-17A is a prevalent inflammatory cytokine involved in the promotion of diabetes-mediated retinal inflammation and the progression of diabetic retinopathy. The primary source of IL-17A is Th17 cells, which are T helper cells that have been differentiated by dendritic cells in a proinflammatory cytokine environment. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can manipulate dendritic cell maturation, halt the production of IL-6 (a proinflammatory cytokine), and suppress Th17 cell differentiation. In the current study, we examined the efficacy of an AhR agonist, VAF347, as a potential therapeutic for the onset of non-proliferative diabetic retinopathy in streptozotocin (STZ)-induced diabetic C57BL/6 mice. We determined that diabetes-mediated leukostasis, oxidative stress, and inflammation in the retina of STZ-diabetic mice were all significantly lower when treated with the AhR agonist VAF347. Furthermore, when VAF347 was subcutaneously injected into STZ-diabetic mice, retinal capillary degeneration was ameliorated, which is the hallmark of non-proliferative diabetic retinopathy in this diabetes murine model. Collectively, these findings provide evidence that the AhR agonist VAF347 could be a potentially novel therapeutic for non-proliferative diabetic retinopathy.
Highlights
With 463 million diabetics in the world, diabetes is one of the most prevalent noncommunicable diseases worldwide [1,2,3]
The most prevalent source of IL-17A is CD4+ T helper-17 (Th17) cells, which are RORγt+ T cells that have been differentiated by dendritic cells in a proinflammatory cytokine environment [13,14]
We examined an aryl hydrocarbon receptor (AhR) agonist, VAF347, that can inhibit Th17 cell differentiation as another potentially novel therapeutic for diabetic retinopathy
Summary
With 463 million diabetics in the world, diabetes is one of the most prevalent noncommunicable diseases worldwide [1,2,3]. Previous studies have provided evidence that diabetes mediates chronic, low-grade inflammation, which leads to vascular impairment in the heart, kidney, and retina [4,5,6]. In diabetes, IL-17A is constantly produced and inflammation does not halt, which can lead to kidney failure, heart disease, or vision loss [4,5,6,9]. In the retina, these microvascular alterations can induce capillary non-perfusion and the onset of diabetic retinopathy, which is the leading cause of blindness in the working-age population worldwide [2,10]. When diabetes-mediated IL-17A production was ablated by therapeutically inhibiting
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