When there is an injury in the eye or other parts of the body, immune cells in the blood, known as neutrophils, respond. It’s a different story with the retina. When the retina’s photoreceptor cells are damaged, it is the microglia, the brain’s immune cells, that respond and the neutrophils aren’t called into action. In addition, because the retina is exposed to light and has high metabolic activity, it is vulnerable to oxidative stress and DNA damage as a result of aging. How do the immune response in the retina and DNA damage contribute to eye disease, and how can these mechanisms be utilized to better understand how eye diseases occur and eventually lead to treatments for eye disease. Research at the University of Rochester and the University of California, Irvine have shed light on both questions, and the findings are surprising.
When the Neutrophils Don’t Respond
As stated earlier, when the retina is damaged it is the microglia that respond, not the neutrophils. What makes this surprising is that the neutrophils are nearby and do respond when other parts of the eye are damaged. Why is that and how can this be used to develop treatments that work within this framework?
Researchers at the University of Rochester used adaptive optics imaging technology to observe single neurons and immune cells in the living eye of laboratory mice with photoreceptor damage. They found that although both the neutrophils and microglia are present in the retina, the microglia do not recruit the neutrophils to help repair photoreceptor damage. Researchers feel this suggests a kind of “cloaking” mechanism that happens during an injury to the retina to protect it from an influx of immune cells could cause a great deal of harm.
What makes this noteworthy is that the neutrophils are so close to the microglia, but the microglia don’t signal them to assist in injury repair. This work shows that it is possible to see how individual cells communicate as the retina reacts to damage.
DNA Damage
A research team at the University of California, Irvine (UC Irvine) found that accumulated DNA damage in the retina contributes to age-related macular degeneration (AMD). They also found that targeting specific retinal cells may lead to therapies that slow or stop disease progression.
“Because age is the strongest risk factor for AMD, gaining deeper insights into the underlying biology of aging in the eye is essential for developing effective therapies,” said co-corresponding author Dorota Skowronska-Krawczyk, UC Irvine associate professor of physiology and biophysics.
The retina uses more oxygen than most other tissues in the body and relies on the retinal pigment epithelium cell layer to work properly. In addition, the retina’s exposure to both light and high metabolic activity makes it vulnerable to oxidative stress and the buildup of DNA damage, both of which are linked to aging. Scientists wanted to understand how the relationship between the retina, the retinal pigment epithelium and the biological mechanisms that lead to age-related changes in order to develop new treatment approaches for AMD.
Scientists studied a mouse model with reduced levels of ERCC1-XPF, a DNA repair enzyme, and compared both young, healthy mice and naturally aging mice. At three months of age, the model showed signs of visual impairment, structural changes in the retina and abnormal blood vessel formation. It also showed changes in gene expression and mitochondrial dysfunction in the retinal pigment epithelium. These mirror changes seen in human eye aging.
This is significant since the more that scientists learn about how DNA damage contributes to AMD and other eye diseases, the better equipped they will be to develop the treatments that address the root causes of vision loss. Potential strategies include ways to enhance DNA repair or removing damaged cells before they cause harm. Researchers plan to study which cell types lead to age-related changes by selectively impairing DNA mechanisms. The goal is to advance the development of therapies that reduce the burden of age-related vision loss and improve quality of life.
Research at University of Rochester and the University of California, Irvine has shown that there is more than one way for vision impairment and blindness to occur and there is more than one way to restore vision. Whether thought modulating the immune response or fixing damaged DNA, research is paving the way to improved outcomes for people with vision diseases.