New focus on ocular inflammation and possible therapeutic pathways

A new study published in The American Journal of Pathology provides new evidence that immune cells enter the retina via the body's standard pathway, identifying Platelet Endothelial Cell Adhesion Molecule (PECAM; also known as CD31) as the gatekeeper and neutrophils as proresolving mediators. This research offers new insights into how eye inflammation develops and could lead to better-targeted treatment options.

This is adapted from Medical Xpress.

As part of an effort to understand the molecules and mechanisms that regulate transendothelial migration in different vascular beds of the body, researchers focused on the blood vessels of the retina, part of the blood-brain barrier. Transendothelial migration is the process by which white blood cells migrate out of the blood into tissue to reach sites of inflammation. The researchers found that white blood cells pass through the blood-retinal barrier via the same mechanism as they do throughout the rest of the body.

In the United States, infectious uveitis (eye inflammation) affects 19 in 100,000 people per year. The burden is significantly higher in resource-limited settings, where infection accounts for an estimated 30% to 60% of uveitis cases. Infectious uveitis can take four to six weeks to resolve when treated. It rarely resolves on its own and can often turn into a chronic, recurring condition.

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Studying the inflammatory response using histology and flow cytometry, investigators were able to characterize how, when and where white blood cells enter the eye after inducing acute uveitis in mice by injecting bacterial endotoxin into the vitreous of the eye to mimic infection. In line with previous research, they found that neutrophils act as the first responders in the early stages of inflammation and help recruit a second wave of white blood cells called monocytes. After 48 hours, neutrophils were almost absent in the retina. The monocytes then developed into macrophages, which remained in the retina for at least 72 hours.

When the researchers selectively removed neutrophils from the blood, this paradoxically led to an increase in monocytes entering the retina, suggesting that the presence of neutrophils somehow limited their recruitment.

The study demonstrates for the first time that the gateway that enables the transmigration of leukocytes from the blood vessels into retinal tissue is platelet endothelial cell adhesion molecule (PECAM)-dependent—the same pathway found throughout the rest of the body's systemic circulation.

When mice were treated with a blocking monoclonal antibody against PECAM, it led to significantly reduced numbers of neutrophils, T cells and monocytes entering the retina. Rather than completely depleting neutrophils and stripping away their proresolving properties, targeting PECAM controlled white blood cell traffic and translated into improved clinical outcomes in this model of uveitis.

Ref: 1; 2

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