CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice.

Aicha Saadane, Alexander A Veenstra, Martin S Minns, Jie Tang, Yunpeng Du, Fatima Abubakr Elghazali, Emma M Lessieur, Eric Pearlman, Timothy S Kern

Diabetologia 2023 Mar

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Accumulating evidence suggests that leucocytes play a critical role in diabetes-induced vascular lesions and other abnormalities that characterise the early stages of diabetic retinopathy. However, the role of monocytes has yet to be fully investigated; therefore, we used Ccr2-/- mice to study the role of CCR2+ inflammatory monocytes in the pathogenesis of diabetes-induced degeneration of retinal capillaries. Experimental diabetes was induced in wild-type and Ccr2-/- mice using streptozotocin. After 2 months, superoxide levels, expression of inflammatory genes, leucostasis, leucocyte- and monocyte-mediated cytotoxicity against retinal endothelial cell death, retinal thickness and visual function were evaluated. Retinal capillary degeneration was determined after 8 months of diabetes. Flow cytometry of peripheral blood for differential expression of CCR2 in monocytes was assessed. In nondiabetic mice, CCR2 was highly expressed on monocytes, and Ccr2-/- mice lack CCR2+ monocytes in the peripheral blood. Diabetes-induced retinal superoxide, expression of proinflammatory genes Inos and Icam1, leucostasis and leucocyte-mediated cytotoxicity against retinal endothelial cells were inhibited in diabetic Ccr2-deficient mice and in chimeric mice lacking Ccr2 only from myeloid cells. In order to focus on monocytes, these cells were immuno-isolated after 2 months of diabetes, and they significantly increased monocyte-mediated endothelial cell cytotoxicity ex vivo. Monocytes from Ccr2-deficient mice caused significantly less endothelial cell death. The diabetes-induced retinal capillary degeneration was inhibited in Ccr2-/- mice and in chimeric mice lacking Ccr2 only from myeloid cells. CCR2+ inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy. © 2022. The Author(s).

Citation

Aicha Saadane, Alexander A Veenstra, Martin S Minns, Jie Tang, Yunpeng Du, Fatima Abubakr Elghazali, Emma M Lessieur, Eric Pearlman, Timothy S Kern. CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice. Diabetologia. 2023 Mar;66(3):590-602