Mouse Study Identifies PECAM as Gatekeeper for Immune Cells Entering the Retina

A new study published in The American Journal of Pathology finds that immune cells enter the retina through the same pathway used throughout the rest of the body. Researchers at Northwestern University Feinberg School of Medicine identified platelet endothelial cell adhesion molecule (PECAM) as the gatekeeper, and found neutrophils act as proresolving mediators that help inflammation subside.

The team studied transendothelial migration -- how white blood cells move from blood vessels into tissue to reach inflammation -- in retinal blood vessels, part of the blood-brain barrier. In the United States, infectious uveitis, eye inflammation caused by infection, affects 19 in 100,000 people per year; in resource-limited settings, infection causes an estimated 30% to 60% of uveitis cases. Treated infectious uveitis can take four to six weeks to resolve, rarely clears on its own, and can become chronic and recurring. Current treatments -- corticosteroids and anti-infective drugs -- are limited by side effects, said William A. Muller of Northwestern.

Using histology and flow cytometry, the team induced acute uveitis in mice by injecting bacterial endotoxin into the eye's vitreous to mimic infection, then tracked when and where white blood cells entered the eye. Neutrophils arrived first and helped recruit a second wave of cells called monocytes; by 48 hours, neutrophils were almost gone from the retina. Monocytes then became macrophages, staying in the retina at least 72 hours. Removing neutrophils from the blood paradoxically increased monocyte entry, suggesting neutrophils normally limit monocyte recruitment, possibly through proresolving mediators they secrete, Muller said.

The study showed for the first time that this gateway into retinal tissue is PECAM-dependent, the same pathway used elsewhere in the body. In mice given a blocking monoclonal antibody against PECAM, fewer neutrophils, T cells and monocytes entered the retina. Rather than depleting neutrophils, targeting PECAM controlled white blood cell traffic and improved clinical outcomes in this mouse model of uveitis, said Vivienne Fang Shaver, a Northwestern Ph.D. candidate.