Abstract
Purpose :
Accumulating evidence suggests that leukocytes play a critical role in diabetes-induced vascular lesions and other abnormalities that characterize the early stages of diabetic retinopathy (DR). However, it is not clear which subset of leukocytes is involved in this process, here we used Ccr2-/- mice to study the role of CCR2+ monocytes in the pathogenesis of the retinopathy.
Methods :
Experimental diabetes was induced in wild-type (WT) and Ccr2-/- mice using streptozotocin. After 2 months of diabetes, superoxide levels, expression of inflammatory proteins, leukostasis, leukocyte- and monocyte-mediated cytotoxicity against retinal endothelial cell (EC) death, retinal thickness, and visual function were evaluated using published techniques. Retinal capillary degeneration was determined after 8 months of diabetes. Flow cytometry of peripheral blood for differential expression of CCR2 in monocytes was determined.
Results :
In nondiabetic mice, CCR2 was highly expressed on monocytes, and Ccr2-/- mice lack Ccr2+ monocytes in the peripheral blood. The diabetes-induced retinal superoxide, expression of pro-inflammatory proteins (iNOS and ICAM-1), leukostasis, and leukocyte-mediated cytotoxicity against retinal EC 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 EC cytotoxicity ex vivo. Monocytes from Ccr2-deficient mice caused significantly less EC death. The diabetes-induced retinal capillary degeneration was inhibited in Ccr2-/- mice and in chimeric mice lacking Ccr2 only from myeloid cells.
Conclusions :
Ccr2-deletion inhibits the development of retinal vascular lesions (presumably via the population of monocytes that express the Ccr2 protein). Thus, Ccr2+ myeloid cells (mainly monocytes) contribute to the pathogenesis of early lesions of DR.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.