Immune cell regeneration in mouse retina

Images of mouse retina after being treated with a drug that nearly eliminates immune cells called microglia. After treatment ended, nearly all microglia were gone (day 0). Seven days later, microglia had migrated across the retina, and by day 10 they increased in number.Wai T. Wong, National Eye Institute

The retina is a thin layer of cells at the back of the eye. It includes light-sensing cells and neurons that transmit visual information to the brain. Mixed in with these cells are microglia, specialized immune cells that help maintain the health of the 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, microglia also work to remove unhealthy or dying cells at the injury site. But microglia can target healthy cells and contribute to vision loss.

Studies show that in degenerative retinal disorders, like age-related macular degeneration and retinitis pigmentosa, blocking or removing microglia can help slow vision loss. Loss of microglia for a short time doesn’t affect the function of neurons. Thus, removing them temporarily might be a useful treatment for such retinal disorders.

To test what happens in the retina after microglia have been eliminated and whether the cells can return to their normal arrangement and functions, a team led by Dr. Wai T. Wong of NIH’s National Eye Institute (NEI) depleted microglia in the retinas of mice. Results were published in Science Advances on March 21, 2018.

The researchers eliminated microglia using either a genetically engineered mouse or a drug that blocks a signal that microglia depend on for survival. With either approach, the microglia repopulated the retina within 30 days after being eliminated. The cell population returned to normal density after 150 days in both the drug and genetic models.

The team used a novel method to visually track microglial movements in the retina. They found that the returning microglia first grew in clusters near the optic nerve, the cable-like bundle of nerve fibers that carries signals from the retina to the brain. Gradually, new microglia expanded outward toward the edges of the retina. Over time, the cells re-established evenly throughout the retina.

To test whether the new microglia were fully functional, the scientists damaged the retina with bright light. The new microglia were able to activate and migrate to the injury site normally. The researchers also tested the health of different groups of neurons and found that the microglia fully maintained the function of neurons in the retina. This was especially the case when the depletion was short-lived.

Further work showed that a molecule called CX3CL1 played a significant role in microglial repopulation in the mouse retina. Mice genetically engineered to lack this molecule had delayed microglial repopulation.

“Our study is foundational for understanding ways to control the immune system in the retina,” Wong says.

The drugs used to remove microglia were administered systemically, affecting the brain and other parts of the central nervous system. More research is needed to find ways to administer these drugs directly to the retina, sparing off-target tissues.