RBP4 Aggravates Diabetic Retinopathy by Inducing Microglial Activation and Endothelial Inflammation

Diabetic retinopathy (DR) is recognized as an inflammatory neurovascular complication, with neuronal deficits preceding vascular symptoms. This study identified elevated serum retinol-binding protein 4 (RBP4) as a risk factor for DR, because it induces retinal neuronal injuries and exacerbates vascular defects. Vitreous RBP4 levels were significantly elevated in patients with DR compared with those with macular disease. Elevated vitreous and serum RBP4 levels exacerbated hyperglycemia-induced endothelial inflammation, retinal vascular leakage, pericyte loss, and acellular capillaries in streptozotocin-induced diabetic mice. Progressive retinal degeneration and impaired electroretinography function were exhibited with RBP4 overexpression, likely through inducing retinal microglial activation and phagocytosis. Microglial depletion via PLX3397 (CSF-1R inhibitor) or inhibition using minocycline (anti-inflammatory tetracycline) significantly mitigated retinal degeneration in RBP4 transgenic (RBP4-Tg) mice. Furthermore, minocycline abolished the enhanced phagocytosis of zymosan in murine microglial BV2 cells induced by RBP4. The application of TAK242 or use of microglia-specific TLR4 knockout markedly reduced retinal neuroinflammation and degeneration in RBP4-Tg mice. Overall, these results suggest that elevated serum and vitreous RBP4 levels may be a risk factor for DR by exacerbating retinal neuronal and vascular injuries. ARTICLE HIGHLIGHTS: Retinol-binding protein 4 (RBP4) levels are elevated in the vitreous humor of patients with diabetic retinopathy (DR) and in RBP4 transgenic mice. Elevated vitreous RBP4 exacerbates both vascular and neuronal deficits associated with DR in streptozotocin-induced diabetic mice. Hyperglycemia augments the RBP4-induced inflammatory response in retinal microvascular endothelial cells to exacerbate DR-related vascular pathologies. RBP4 triggers retinal microglial activation and phagocytosis via TLR4/nuclear factor-κB/mitogen-activated protein kinase pathway, and microglial depletion or inhibition alleviates RBP4-induced retinal neurodegeneration.