The Eyes Have It: New Research Reveals Underlying Mechanisms of Eye Inflammation (Uveitis)

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 our body. This studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, provides new insights into how eye inflammation develops and could lead to better targeted treatment options.

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.

“Currently, treatments for uveitis include corticosteroids and broad-spectrum anti-infective drugs, but these are limited by side effects and systemic complications,” explains William A. Muller, MD, PhD, Department of Pathology and Center for Human Immunology, Northwestern University, Feinberg School of Medicine. “A better understanding of the underlying mechanisms of infectious uveitis could lead to more effective therapies, which is particularly important in underdeveloped parts of the world.”

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.

Dr. Muller notes, “We are beginning to realize that neutrophils that enter a site of inflammation also secrete proresolving mediators that help to limit inflammation and promote recovery. It is very possible that in the absence of these mediators, there were fewer anti-inflammatory molecules to ‘put the brakes on’ monocyte recruitment.”

The study demonstrates for the first time that the gateway that enables the transmigration of leukocytes from the blood vessels into the retina’s 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.

“Our findings show that despite the retina’s unique, highly protected environment, it relies on the same PECAM-dependent mechanism to manage immune cell traffic,” concludes Vivienne Fang Shaver, MD, PhD candidate, Department of Pathology and Medical Scientist Training Program, Northwestern University, Feinberg School of Medicine. “Depleting neutrophils would never be a safe strategy to treat a non-life-threatening disease. Therefore, our focus was directed toward developing a therapeutically relevant model. Understanding the molecules and mechanisms that regulate this cell migration is a crucial first step towards developing targeted treatment options for uveitis.”

Notes for editors

The article is “Platelet Endothelial Cell Adhesion Molecule—Dependent Leukocyte Transmigration Is an Essential Early Event in Endotoxin-Induced Uveitis,” by Vivienne Fang Shaver, Maureen E. Haynes, Meital A. Gewirtz, David P. Sullivan, Jeremy A. Lavine, and William A. Muller (https://doi.org/10.1016/j.ajpath.2026.03.010opens in new tab/window). It appears online in The American Journal of Pathology, ahead of volume 196, issue 10 (October 2026), published by Elsevier.

The article is openly available for 60 days at https://ajp.amjpathol.org/article/S0002-9440(26)00093-3/fulltextopens in new tab/window. It is part of a review series on pathobiology, mechanisms, and innovations in ocular disease.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors, contact William A. Muller, MD, PhD, at [email protected]opens in new tab/window, or Vivienne Fang Shaver, MD, PhD candidate, at [email protected]opens in new tab/window.

This study was supported by NIH National Eye Institute grants F30EY036261, T32EY025202, and R01EY034486, NIH National Heart, Lung, and Blood Institute grants F31HL172345 and R35HL155652, and NIH National Institute on Aging grant R21AG086751.

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.orgopens in new tab/window

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