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

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  • Additional Information
    • Source:
      Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE
    • Publication Information:
      Original Publication: Berlin Springer Verlag
    • Subject Terms:
      Diabetic Retinopathy*/metabolism ; Retinal Degeneration*/metabolism ; Diabetes Mellitus, Experimental*/metabolism; Animals ; Mice ; Monocytes/metabolism ; Endothelial Cells/metabolism ; Superoxides/metabolism ; Mice, Inbred C57BL ; Retinal Vessels/pathology ; Receptors, CCR2/genetics ; Receptors, CCR2/metabolism
    • Abstract:
      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 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.
      Conclusions/interpretation: CCR2 + inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy.
      (© 2022. The Author(s).)
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    • Grant Information:
      R01 EY022938 United States EY NEI NIH HHS; R01 EY033002 United States EY NEI NIH HHS
    • Contributed Indexing:
      Keywords: CCR2; Diabetic retinopathy; Leucocytes; Leucostasis; Monocytes; Retinal capillary degeneration; Superoxide
    • Accession Number:
      11062-77-4 (Superoxides)
      0 (Ccr2 protein, mouse)
      0 (Receptors, CCR2)
    • Publication Date:
      Date Created: 20230125 Date Completed: 20230203 Latest Revision: 20230322
    • Publication Date:
      20250114
    • Accession Number:
      PMC9892100
    • Accession Number:
      10.1007/s00125-022-05860-w
    • Accession Number:
      36698021