Investigators from the National Eye Institute suggest a signaling pathway controlled by transforming growth factor beta (TGF-beta) may influence age-related macular degeneration (AMD) progression. Their study, published in ELife, found that interrupting TGF-beta sent a signal for immune cells to activate and, in turn, cause inflammation in some cases. The immune cells, known as microglia, can damage the retina when activated. Researchers likened the damage to the cellular effects found in AMD.

Research into the communication between microglia and retinal neurons is ongoing. As such, researchers wanted to discover the possibility of a link between TGF-beta and abnormal retinal microglia, which are often found in AMD.

When a retina is healthy, neurons constantly release TGF-beta and other signaling molecules that let neighboring cells know everything is normal. If the signals change and microglia become activated, they move to injured areas to remove damaged or dead cells, the researchers noted in their paper.

The study used genetically modified mice in which investigators could turn off the microglial cells’ ability to sense TGF-beta. Investigators found when the cells stopped detecting TGF-beta, they immediately changed shape, moved to incorrect locations and began to proliferate.

Interestingly, the microglia also decreased their sensome—a collection of proteins microglia use to sense their environment—and began expressing proteins used in their activated state.

While microglia are critical for maintaining healthy neurons, decreased TGF-beta activity switches microglia to a pro-inflammatory mode, which is worse than having no microglia at all, the researchers commented.

Additionally, the study reported another group of retinal support cells, Müller glia, began to show signs of distress, and retinal neurons began to fail and die. Abnormal microglia drastically exacerbated the growth of new blood vessels in a model of AMD.

All these pathological changes were similar to what happens in the progression of late AMD, indicating that microglia and TGF-beta signaling may help drive disease progression in humans, the study reported. 

Researchers added they don’t believe TGF-beta signals are completely missing in AMD, but small changes in the strength of the TGF-beta signal could be disrupting the fine balance in signaling immune cells that microglia require for optimal function. An imbalance in these signals over time can lead to a slow progression toward disease.

Researchers concluded TGF-beta may represent an important therapeutic target for treating AMD.

Ma W, Silverman S, Zhao L, et al. Pathological transformation of retinal microglia in the absence of constitutive TGF-beta signaling induces retinal degeneration and exacerbates choroidal neovascularization. January 22, 2019. ELife. [Epub ahead of print].