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E. L. Granger, S. K. Bronson, J. K. Krady, S. F. Abcouwer, C. C. Norbury; Identification of a Novel Subset of Activated Microglia in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):173.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy remains the leading cause of blindness in adults. Retinopathy is characterized by vascular permeability, macular edema, and neovascularization. The Ins2+/Akita mouse model, which develops diabetes at 4 weeks of age, shows changes in the retina similar to those of patients with retinopathy. mRNA analysis has revealed an increase in proinflammatory cytokine levels in whole retina of diabetic mice, although the source of these cytokines remains unknown. An increase in inflammatory cytokines can lead to increases in vascular permeability and the infiltration of leukocytes. Retina-resident microglia, the resident macrophage of the central nervous system (CNS), represent a likely source of these proinflammatory cytokines. However, in our previous investigations, microglia displaying an activated morphology comprised only a small portion of the microglia population. Thus, it appears that retinal microglia are not a homogeneous population of cells and identification of the cellular subsets that become activated is necessary to understand the potential role of these cells in the development of diabetic retinopathy.
We isolated microglia and utilized a cytofluorographic analysis to identify microglia subsets and the activation status of these cells in both the retina and the brain, a tissue which is not typically affected during diabetes.
We demonstrated that microglial subset populations in brain and retina differ. We then compared the Ins2+/+ (non-diabetic) and Ins2+/Akita (diabetic) at the onset of diabetes (1 month of age) and at stages leading up to a severely diabetic stage (4 months of age). The distribution of microglial subsets in the retina did not change in Ins2+/+ or Ins2+/Akita mice at any age. Interestingly, we showed that one "classical" subset dramatically upregulated the activation markers, MHC Class II and sialoadhesin. This upregulation was only observed in Ins2+/Akita mice as they approached 4 months of age. Although there was some upregulation of MHC Class II in both the Ins2+/+ and Ins2+/Akita mice with age, there was a very significant increase in the MHC class II expression observed in the Ins2+/Akita mice. The difference in these activation markers was only observed in the retina, not in the brain, indicating that the microglial activation is limited to the retina.
We have demonstrated that a single subset of microglia becomes activated over time in diabetes.
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