No abstract

Inflammation plays an important role in the pathogenesis of diabetic retinopathy (DR). To precisely define the inflammatory mediators, we examined the transcriptomic profile of human retinal endothelial cells exposed to advanced glycation end products which revealed the neutrophil chemoattractant chemokine, CXCL1 as one of the top genes upregulated. The effect of neutrophils in the alteration of BRB was further assessed in wildtype C57BL/6J mice intravitreally injected with recombinant CXCL1 as well as in streptozotocin-induced diabetic mice. Both intravitreally CXCL1-injected and diabetic animals showed a significantly increased retinal vascular permeability with significant increase in infiltration of neutrophils and monocytes in retinas, and increased expression of chemokines and their receptors, proteases, and adhesion molecules. Treatment with Ly6G antibody for neutrophil depletion in both diabetic mice as well as CXCL1-injected animals showed significantly decreased retinal vascular permeability accompanied by decreased infiltration of neutrophils and monocytes, and decreased expression of cytokines and proteases. The CXCL1 level was significantly increased in the serum samples of diabetic retinopathy patients compared to non-diabetic subjects. These data reveal a novel mechanism by which the chemokine CXCL1, through neutrophil recruitment, alters blood retinal barrier in DR, and thus serves as a potential novel therapeutic target.