Immune Cell Age Plays Role In Retinal Damage In Age-related Macular Degeneration

The scientists discovered that specific immune cells called macrophages play a role in the disease process in older mice by failing to block the development of abnormal, leaky blood vessels behind the retina. But in younger mice, macrophages typically prevent abnormal blood vessel formation.

The scientists believe better understanding of how macrophages work may provide potential targets for therapies to slow or even reverse vision loss. The findings are reported in the November issue of the Journal of Clinical Investigation.

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.

Whether the macrophages will block or encourage the growth of damaging blood vessels is related to the subtype of macrophage according to principal investigator Rajendra S. Apte, M.D., Ph.D., assistant professor of ophthalmology and visual sciences.

"There are two basic types of macrophages -- known as M1 and M2 -- and in the older mice, there was a preponderance of cells with the M2 signature," he says. "These M2 cells promoted abnormal blood vessel growth in the eyes of older mice. In younger mice, most macrophages had the M1 signature, and those cells inhibited the development of defective blood vessels."

Apte says it appears the population of macrophages drifts from the M1 type to M2 cells because of an increase in the levels of an immune system molecule called interleukin-10 (IL-10) in the eye as the mice get older. In a previous study, his team had found that high levels of IL-10 interfere with macrophages' ability to regulate blood vessel growth. As mice got older, the animals made more IL-10, and this caused more macrophages to become the M2 type.

"The older mice had much higher levels of IL-10," Apte explains. "That suggests IL-10 may be driving this process because higher IL-10 levels are associated with more M2 macrophages that cannot regulate blood vessel growth, and lack of IL-10, as in genetic knockout mice, leads to a preponderance of M1 macrophages."

The blood vessels that form in age-related macular degeneration are not like the mature vessels found in most of the body. Vessels associated with the disease don't have normal, tight junctions, but rather leak and bleed. They also tend to be located beneath the macula, the center of the retina, and when they bleed, the result is loss of vision.

Just as there are two types of macrophages, there also are two types of macular degeneration: a "dry" form and a "wet" form. Most patients have the dry form of the disease, which sometimes can progress and cause severe vision loss. But between 80 and 90 percent of blindness occurs in the wet form of the disease and is caused by abnormal blood vessel growth beneath the retina.

Apte's team studied both young and old mice whose eyes were treated with a laser that spurs the growth of the damaging blood vessels. Although the acute laser injury is not identical to the chronic damage caused by the disease, Apte says the animal model has been remarkably successful in identifying therapies to treat the blinding eye disease.

Some of the laser-treated mice could not make IL-10. Previously, Apte's team found that mice genetically engineered without IL-10 develop fewer abnormal vessels beneath the retina. That also was true in this study. One reason may be that mice without IL-10 have mostly M1 macrophages, which inhibit new blood vessel formation.

It may be true, Apte says, that as people age, they experience increases in IL-10 levels, as well as other cytokines that influence a drift towards M2 macrophages just as the mice do. It's also possible that factors such as smoking, uncontrolled high blood pressure or a genetic pre-disposition may enhance this process.

"It appears from the mice we've studied that the microenvironment in and around the eye might influence how macrophages behave and what subclass of macrophages is likely to be present," Apte says. "We believe this cascade involving IL-10 and macrophages provides potential targets for therapies to prevent some of the devastating vision loss that affects so many patients with age-related macular degeneration and may even be useful in treating other diseases that involve abnormal blood vessel growth, such as cancer and heart disease."

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, pp. 3421-3426, Nov. 2007.

This research was funded by grants from the National Eye Institute (NEI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 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 and an American Federation for Aging Research Grant.