School of Medicine scientists 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, the 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,” said Rajendra S. Apte, M.D., Ph.D., assistant professor of ophthalmology and visual sciences and of developmental biology 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 as interleukin-10 (IL-10), are small proteins that regulate immunity and inflammation. Apte 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. 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 age 50. 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, which afflicts almost 24 million people 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. 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 newborns each year.
To learn what contributes to that abnormal vessel development in the retina, Apte’s team studied mice that began 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 said. “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,” said Dru S. Dace, Ph.D., the paper’s first author and a postdoctoral fellow. “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 said. “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.”