Journal Article

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

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

2023

Overview

Aims/hypothesis 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. Methods 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. Results 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 Ino s 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. Conclusions/interpretation CCR2 + inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy. Graphical abstract

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Animals / Apoptosis / Capillaries / CCR2 protein / Cell death / Cytotoxicity / Degeneration / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - metabolism / Diabetic retinopathy / Diabetic Retinopathy - metabolism / Endothelial cells / Endothelial Cells - metabolism / Flow cytometry / Human Physiology / Inflammation / Intercellular adhesion molecule 1 / Internal Medicine / Leukocytes / Medicine / Medicine & Public Health / Metabolic Diseases / Mice / Mice, Inbred C57BL / Monocyte chemoattractant protein 1 / Monocytes / Monocytes - metabolism / Myeloid cells / Pathogenesis / Peripheral blood / Receptors, CCR2 - genetics / Receptors, CCR2 - metabolism / Retina / Retinal Degeneration - metabolism / Retinal Vessels - pathology / Retinopathy / Streptozocin / Superoxide / Superoxides - metabolism / Visual perception