March 26, 2018Ophthalmology
The retina is a thin layer of cells in the back of the eye that includes light-sensing photoreceptor cells and other neurons involved in transmitting visual information to the brain. Mixed in with these cells are microglia, specialized immune cells that help maintain the health of the retina and the function of retinal neurons. Microglia are also present in other parts of the central nervous system, including the brain. In a healthy retina, communication between neurons and microglia is important for maintaining the neuron's ability to send signals to the brain. When the retina is injured, however, microglia have an additional role: They migrate quickly to the injury site to remove unhealthy or dying cells. However, they can also remove healthy cells, contributing to vision loss. Studies show that in degenerative retinal disorders like age-related macular degeneration (AMD) and retinitis pigmentosa (RP), inhibiting or removing microglia can help retain photoreceptors, and thus slow vision loss. But return of microglia is still important to support the retina's neurons.
According to an article published online in Science Advances (21 March 2018), microglia can completely repopulate themselves in the retina after being nearly eliminated. The cells also re-establish their normal organization and function. The findings point to potential therapies for controlling inflammation and slowing progression of rare retinal diseases such as RP and AMD, the most common cause of blindness among Americans 50 and older.
The authors were interested in understanding what happens in the retina after microglia have been eliminated, particularly whether the cells could return to their normal arrangement and fulfill their normal functions. To test this, they depleted the microglia in the retinas of mice using the drug PLX5622 (Plexxikon), which blocks the microglial CSF-1 receptor. Microglia depend on continuous signals through this receptor for survival. Interruption of this signaling for several days caused the microglia to nearly disappear, leaving just a few cells clustered around the optic nerve -- the cable-like bundle of nerve fibers that carries signals from the retina to the brain. Since loss of microglia for a short time doesn't affect the function of neurons, removing microglia temporarily -- in order to reduce inflammation for example -- could potentially be useful as a therapeutic intervention for degenerative or inflammatory disorders of the retina.
Within 30 days after stopping the drug, the authors found that the microglia had repopulated the retina, returning to normal density after 150 days. Using a novel method for visually tracking microglial movements in the retina, they determined that the returning microglia initially grew in clusters near where the optic nerve leaves the eye. Gradually, new microglia expanded outwards towards the edges of the retina. Over time, the cells re-established an even distribution across and through the various layers of the retina.
To test whether the new microglia were fully functional, the authors used an injury model where photoreceptor cells are damaged by bright light. The new microglia were able to activate and migrate to the injury site normally. In addition, using electroretinography (ERG), a technique that measures the electrical signals generated by retinal neurons after being stimulated with light, the researchers tested the health of different groups of neurons. They found that the microglia were able to communicate with and fully maintain the function of neurons in the retina, especially when the depletion was short-lived.
Drugs that remove microglia are now administered systemically, affecting the brain and other parts of the central nervous system. According to the authors, more research is needed to find ways to administer these drugs directly to the retina, sparing off-target tissues.