In uveitis, immune cells must cross the blood-retina barrier before they can contribute to tissue inflammation. New preclinical research suggests that interrupting this migration – rather than broadly suppressing the immune response – could represent a potential strategy for limiting disease.
Researchers at Northwestern University in Chicago investigated the role of neutrophils, or polymorphonuclear leukocytes (PMNs), in a mouse model of endotoxin-induced uveitis (EIU). The model is used to study mechanisms relevant to infectious uveitis, in which neutrophils are among the earliest immune cells recruited to the eye.
The team first examined whether neutrophils help recruit CCR2-positive classical monocytes, another pro-inflammatory cell population. Contrary to expectations, depleting neutrophils before inducing EIU increased CCR2-positive monocyte infiltration into the retina at 24 hours, with the increase persisting at 72 hours.
Although neutrophil depletion significantly improved histologic measures of uveitis, it did not produce a significant improvement in clinical scores. The authors suggested that the increased influx of CCR2-positive monocytes may have compensated, at least partly, for the loss of neutrophils.
Because depleting neutrophils would not be a clinically realistic treatment for uveitis, the researchers next focused on preventing leukocytes from entering retinal tissue. They targeted platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), which facilitates leukocyte transmigration across endothelial cells.
Treatment with an anti-PECAM antibody significantly inhibited transmigration of neutrophils and T cells into the retina. Confocal imaging showed neutrophils apparently trapped within retinal vessels rather than entering the surrounding tissue, providing direct evidence that retinal neutrophil transmigration is PECAM dependent.
The effect translated into improved disease measures. Compared with control-treated animals, mice receiving anti-PECAM had significantly lower blinded clinical scores, while histologic assessment also showed reduced leukocyte infiltration, edema, and hemorrhage.
Overall, PECAM blockade inhibited approximately 64 percent of neutrophil transmigration – sufficient to improve both clinical and histologic manifestations of EIU. The study authors argue that selectively limiting leukocyte entry into ocular tissue could theoretically preserve more systemic immune function than broader immunosuppressive approaches, although this remains to be tested directly.
Important limitations remain. The work was conducted in an acute mouse model, anti-PECAM was administered before symptoms developed, and the investigators examined retinal vasculature rather than leukocyte trafficking throughout the uvea. Further studies will therefore be needed to determine whether the mechanism can be translated into a practical treatment for human uveitis.
