Abstract
Purpose :
Tractional retinal detachment is a vision-threatening complication of advanced diabetic retinopathy. Retinal fibrosis, characterized by fibroblasts, myofibroblasts, and extracellular matrix formation, occurs on the surface of the retinas following retinal neovascularization and vitreous hemorrhage. We have previously shown the contribution of CXCL1 in the blood-retinal barrier alteration in an animal model of diabetic retinopathy. We evaluated the hypothesis that the CXCL1/neutrophil signaling pathway contributes to the development of retinal fibrosis in diabetic retinopathy.
Methods :
The following groups of animals were used: A) Streptozotocin-induced diabetic mice (3 months) vs. diabetic mice treated with neutrophil-depleting Ly6G-1A8 antibody (50ug) for 15 days (n=10); B) Wildtype C57BL/6 J mice intravitreally (IVT) injected with recombinant CXCL1 (100 ng/eye) vs. animals pretreated with Ly6G-1A8 antibody (50ug) followed by IVT treatment with recombinant CXCL1 (n=10). The mRNA expression of late fibrosis markers and late endothelial mesenchymal transition (EndoMT) markers were analyzed using real-time PCR.
Results :
Retinas of both diabetic and intravitreally CXCL1 injected mice showed increased mRNA expression of TGFb1, the primary driver of fibrosis, and late-stage EndoMT markers (MMP2, MMP9, ICAM1, VCAM1, and VE-Cad). The Ly6G-1A8 antibody treatment that depletes neutrophils significantly reduced retina fibrosis markers.
Conclusions :
Overall, we have shown evidence that neutrophil infiltration triggered by CXCL1 in diabetes plays an essential role in EndoMT markers and fibrosis expression. Targeting the CXCL1/CXCR2 receptor pathway may be a potential therapeutic approach in preventing retinal fibrosis formation and retinal detachment traction.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.