Scientists at Washington University School of Medicine in St. Louis have determined that the same factors play key roles in three different diseases that can lead to blindness. In age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity, abnormal blood-vessel growth threatens vision.
Reporting in the journal PLoS One, Washington University vision scientists say that although the mechanisms are a bit different, all three retinal diseases involve the same immune-system factors.
“The offending immune system cell and cytokine are identical,” says Rajendra S. Apte, M.D., Ph.D., a Washington University retina specialist at Barnes-Jewish Hospital and the study’s senior investigator. “Immune cells called macrophages and the cytokine interleukin-10 spur the development of the damaging blood vessels.”
Cytokines, such interleukin-10 (IL-10), are small proteins that regulate immunity and inflammation. Apte, an assistant professor of ophthalmology and visual sciences and of developmental biology, previously found in mice that IL-10 contributes to abnormal blood vessel growth by interacting with macrophages in the eye, leading to growth beneath the mouse retina. Exactly the same thing happens in patients who have the “wet” form of macular degeneration.
Age-related macular degeneration is the leading cause of blindness in the United States in people over the age of 50. It accounts for more than 40 percent of blindness among the elderly in nursing homes, and as baby boomers get older, the problem is expected to grow, with at least 8 million cases predicted by the year 2020.
In diabetic retinopathy, new vessels also form and contribute to vision loss. One difference is that those vessels don’t develop beneath the retina. They grow into the retina. Diabetic retinopathy is a problem for 20 percent of all patients with diabetes, and almost 24 million people have diabetes in the United States alone. Even with laser surgery, many diabetic retinopathy patients experience loss in peripheral and night vision.
A similar condition, called retinopathy of prematurity, occurs when premature babies with immature retinas experience an obstruction in blood flow into the retina called ischemia. In response, those children often develop abnormal blood vessels in the retina that can cause retinal detachment and interfere with vision. Worldwide, the condition blinds 50,000 newborn babies each year.
To learn what contributes to that abnormal vessel development in the retina, Apte’s team studied mice that begin their lives in an environment very high in oxygen and then are returned to normal oxygen levels.
“Because the young mice are accustomed to a high-oxygen environment, the retina perceives normal air as low in oxygen,” Apte explains. “The retina’s response is to produce new blood vessels.”
To look at the role of IL-10 and macrophages, Apte’s team compared normal mice to mice genetically engineered without the ability to make IL-10. When taken out of their oxygen-rich environment, mice with normal IL-10 levels grew many new blood vessels (a process called angiogenesis) in the retina, but the mice that didn’t make IL-10 developed significantly fewer new blood vessels. As with macular degeneration, the IL-10 spurred growth of those vessels by activating macrophages.
“IL-10 promotes the macrophages to make pro-angiogenic molecules, which spur the development of abnormal vessels,” says Dru S. Dace, Ph.D., the paper’s first author and a post-doctoral fellow in Apte’s lab. “After exposure to IL-10, normal mice manufacture pro-angiogenic molecules, but IL-10 knockout mice don’t.”
Dace found that levels of two molecules — vascular endothelial growth factor (VEGF) and nitric oxide — increased substantially in response to IL-10. Both VEGF and nitric oxide are known to promote the formation of new blood vessels.
“When we talk about these blinding diseases, the mechanisms inducing angiogenesis may not be exactly the same in a premature baby and a 70-year-old person,” Apte says. “But it’s important to note that the two key players — macrophages and interleukin-10 — appear to be the prime movers in this process of damaging blood vessel formation in all of these potentially blinding diseases.”
Apte says he wants to learn more about what causes macrophages to change their gene-expression patterns and make more nitric oxide and VEGF. He’d also like to study how those genes function differently in humans with macular degeneration, diabetic retinopathy and retinopathy of prematurity.
He believes therapies that interfere with the IL-10/macrophage pathway might help prevent vision loss.
“These are local diseases, so you wouldn’t want to affect systemic levels of IL-10,” Apte says. “But local, targeted therapy that disrupts signaling pathways mediated by IL-10 or that disrupt the normal function of macrophages in the retina would be an attractive avenue for therapy.”
Dace DS, Khan AA, Kelly J, Apte RS. Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development, Public Library of Science; 3(10), Oct.13, 2008.
The paper is available on-line at http://dx.plos.org/10.1371/journal.pone.0003381.
(related paper) Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice, Journal of Clinical Investigation; vol. 117(11), pp. 3421-3426, Nov. 2007.
(related paper) Apte RS, Richter J, Herndon J, Ferguson TA. Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PloS Medicine, vol. 3:8, Aug. 15, 2006. The paper is available on-line at http://dx.doi.org/10.1371/journal.pmed.0030310.
This research was funded by grants from the National Eye Institute (NEI) of the National Institutes of Health, a Carl Marshall Reeves and Mildred Almen Reeves Foundation Inc. Award, a Research to Prevent Blindness Career Development Award, an American Federation for Aging Research Grant, a grant from the Knights Templar Eye Foundation Inc. and an International Retina Research Foundation Alston Callahan Scholar Award.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.