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Arup Das, Finny Monickaraj, Srinivasa Rao Oruganti, Carolina Franco Nitta, Paul McGuire, Amy Lucero; Chemokine CCL2 (chemokine ligand): Potential Novel Therapeutic Target in Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1273.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously shown that chemokines (CCL2) (monocyte chemoattractant protein-1) play an important role in monocyte trafficking into the retina and alteration of the BRB in animal models of diabetic retinopathy. In this study, we examined the effect of targeting the chemokine pathway to reverse the increased retinal vascular permeability as seen in diabetic retinopathy.
C57/BL6 mice were made diabetic by five daily consecutive intraperitoneal injections of streptozotocin (50 mg/kg/day). After 4 months of diabetes, mice (n =10) were treated by intraperitoneal injections of TAK-779 (a dual CCR2/CCR5 inhibitor) (30 mg/kg) daily for 2 weeks. A control group of diabetic mice (n =10) received IP injections of the vehicle (water), and a third group of non-diabetic mice (n =10) were also used as controls. Retinal vascular permeability was assessed by Western blot analysis for total retinal albumin leakage. Viable retinal single cell suspensions were surface stained using fluorescent conjugated monoclonal antibodies CX3CR1-APC and CD11b-PE (marker for macrophage/microglia), and flow cytometry and data acquisition were done.
Injection of the CCR2/CCR5 dual inhibitor significantly decreased retinal vascular permeability in diabetic animals (p = 0.03). Quantification by flow cytometry demonstrated a two-fold increase of CX3CR1+/CD11b+ (macrophage/microglia) cells in retinas of diabetic animals (treated with vehicle) in comparison to control non-diabetic ones. There was a significant reduction in macrophage/microglia infiltration in animals treated with the CCR2/CCR5 inhibitor.
Chemokine-induced increased monocyte trafficking into the retina plays an important role in alteration of the BRB in diabetes. Targeting the chemokine pathway pharmacologically can be used as a novel strategy for upstream inhibition in management of diabetic macular edema.
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