AMD and Lupus Share Inflammatory Pathway

What: An international team of scientists has identified a biological pathway and molecular sensor that induce inflammation in age-related macular degeneration (AMD) and lupus. The findings lend support for new treatment approaches.

Where: Wang S, et al.,”DDX17 Is an Essential Mediator of Sterile NLRC4 Inflammasome Activation by Retrotransposon RNAs,” Science Immunology, 2021.

BrightFocus Connection: Related research by Bradley Gelfand, PhD, assistant professor of ophthalmology at the University of Virginia (UVA) School of Medicine in Charlottesville, VA, was supported in part by a Macular Degeneration Research (MDR) grant In addition, senior author Jayakrishna Ambati, MD, the founding director of UVA’s Center for Advanced Vision Science, is a past MDR grantee.

Why It Is Important: When pathogens such as harmful bacteria or viruses invade the human body, complicated macromolecules called inflammasomes trigger an immune response to fight them off. But inflammasomes also trigger inflammation when no pathogens are present, though precisely how that happens has remained a mystery.

Now an international team of researchers has discovered a pathway and mechanism by which inflammasomes are triggered in the absence of pathogens, and that these disease-activating contributors are shared by AMD and lupus with different results. In lupus, inflammation leads to joint pain, rash, and fever. In AMD, it leads to degeneration of the retinal pigment epithelium (RPE), a layer of cells that nourish and maintain the health of the retina.

In AMD, the pathway begins with cellular stress caused by aging. Stress triggers the production of a special type of ribonucleic acid (RNA), a molecule similar to DNA, called SINE (short interspersed nuclear elements). These RNAs are sensed by an enzyme called DDX17, activating inflammasomes that trigger inflammation.

The work was performed on immune cells isolated from genetically engineered mice, using an advanced, high-throughput technique. Their discovery of the DDX17 “sensor,” or receptor  for SINE RNAs (aka, a receptor is a sort of molecular docking station) is information scientists have been seeking for decades, according to a UVA press release about the achievement, and it greatly furthers understanding of the process that leads to harmful inflammation.   

The finding of a single pathway that contributes to multiple diseases is highly significant and hopeful in that it could mean that drugs formulated to fight one disease may be effective for other diseases that share the same pathway. Gelfand and Ambati explored this hypothesis in previous research using a geographic atrophy model, and showed that two FDA-approved drugs for HIV and hepatitis B can effectively block RPE degeneration (see link to Research in Brief article below.)

These latest findings provide support for a new class of drugs (Kamuvudines) that the team has been developing to treat diseases that share this inflammatory pathway. Clinical trials for use of these drugs in AMD patients are now being designed and may start as early as next year.