Ultrastructural Analysis of Interleukin-1 Beta-induced Leukocyte Recruitment to the Rat Retina

Purpose: To examine, by ultrastructural analysis, the effect of the proinflammatory cytokine interleukin-1 beta (IL-1 beta) on the integrity of the rat retina and blood-retinal barrier (BRB) and to investigate the site of barrier leakage and the path of leukocyte infiltration into the retina.

Methods: After a single injection of IL-1 beta into the vitreous of the Lewis rat, leukocyte recruitment and retinal disease was assessed immediately and at frequent periods up to 14 days after injection by light and electron microscopy and by immunohistochemistry. The integrity of the BRB and the site of barrier disruption were evaluated using the large molecular weight tracer horseradish peroxidase. The phenotype of recruited leukocytes to the retina was assessed by ultrastructural morphology and immunohistochemistry.

Results: At 4 hours after the intravitreal administration of IL-1 beta, leukocytes were observed infiltrating the retina. Leukocyte infiltration increased gradually and peaked between 24 and 48 hours after injection. Associated with this infiltrate were edema and fibrin leakage, indicative of a breakdown in the BRB. This was confirmed by the demonstration of horseradish peroxidase extravasation across the retinal vascular bed, with leakage of the tracer through disrupted endothelial tight junctions. Using immunohistochemical and morphologic criteria, the majority of infiltrating cells were identified as monocytes-macrophages and neutrophils; occasionally, T cells were found. Ultrastructural analysis showed that the majority of cells entered the retina by migrating through retinal endothelial cells and that there was a smaller contribution from the ciliary body.

Conclusions: The administration of IL-1 beta to the vitreous of the Lewis rat causes an acute, reversible retinal inflammatory response that is accompanied by breakdown of the vascular BRB. Interleukin-1 beta induces the recruitment of mononuclear and polymorphonuclear leukocytes that enter the retina predominantly through the retinal vasculature and that appear to migrate through retinal endothelial cells. These results suggest that IL-1 beta may be an important factor in the pathogenesis of human retinal inflammation.