The Role of Prostanoid Signaling in Inflammatory Responses Relevant to Diabetic Retinopathy
Abstract
Diabetic retinopathy (DR) is the leading cause of blindness in working-age Americans, and its disease burden continues to rise as the global prevalence of diabetes grows. Current therapies for DR address only late-stage disease relevant to retinal neovascularization when irreparable retinal damage from aberrant blood vessel growth has already begun. Herein, we investigated prostanoid signaling as a contributor to the inflammatory responses that occur early in DR pathology to identify novel, targeted therapeutic options addressing disease before the most severe risks to vision ensue. In vitro analyses were performed using primary human Müller glia (hMG), primary human retinal microvascular endothelial cells (hRMEC), and primary human retinal pigment epithelial cells (RPE) or a relevant RPE cell line. After stimulating retinal cells in conditions modeling hyperglycemia, dyslipidemia, and chronic inflammation occurring systemically in patients with diabetes, we found that hMG produced highly elevated levels of one prostanoid, PGE2, whereas hRMEC produced elevated levels of PGF2α most consistently. The receptor-specific effects of prostanoid signaling were then evaluated in cell behavior assays relevant to early DR. Proinflammatory cytokine production in hMG was amplified by both PGE2-EP2 and PGF2α-FP signaling. Leukocyte adhesion to hRMEC was increased by PGF2α-FP signaling. Inner blood-retina barrier function modeled by hRMEC was enhanced by PGE2-EP4 signaling, yet, in contrast, outer blood retina barrier function modeled by cultured RPE was weakened by PGE2-EP2 signaling. Together, these results provide initial characterizations of the inflammatory effects of prostanoid signaling pathways in single cell type behaviors that model early DR progression. Modulation of individual prostanoid signaling pathways via selective agonists and/or antagonists may provide a valuable therapeutic strategy for DR management at the earliest stages of disease.
Description
Keywords
Diabetic retinopathy, prostanoid, prostaglandin, ophthalmology, lipid signaling, inflammation, Müller glia, endothelial cell, retinal pigment epithelium, blood-retina barrier