The findings from the study led by researchers at the University of California San Diego could help scientists pinpoint ways to block the inflammatory process, and create better treatments for patients with lupus, who are particularly sensitive to sun, or with a number of other medical conditions.
Related to DNA, RNA molecules switch genes on and off and aid communication between cells. While it was well-known that ultraviolet light can damage DNA, it wasn’t suspected that UV light damages RNA, or that the RNA damage was the signal that led to inflammation.
“This study reveals important roles for the innate immune system and its ability to respond to specific RNA ‘danger signals’ in the inflammatory manifestations of sunburn,” said Greidinger, associate professor of medicine, chief of the Division of Rheumatology and staff physician at the Miami Veterans Affairs Medical Center. “Since patients with lupus may develop especially sun-sensitive skin, flare-ups of their disease after sun exposure, and immune responses against these RNAs and their protein binding partners, this work may improve our understanding of lupus and related autoimmune diseases, and may lead to improved therapies.”
Richard L. Gallo, M.D., Ph.D., chief of the UC San Diego Division of Dermatology and senior author of the study, said the discovery “suggests a way to get the beneficial effects of UV therapy without actually exposing our patients to the harmful UV light. Also, some people have excess sensitivity to UV light, patients with lupus, for example. We are exploring if we can help them by blocking the pathway we discovered.”
Published in the July 8 advance online publication of Nature Medicine, the study, “Ultraviolet radiation damages self noncoding RNA and is detected by TLR3,” specifically showed that the effects of UV light that induces sunburn-associated inflammation were mediated in part by UV-modified forms of U1-RNA and Toll-like receptor 3 (TLR3). The backbone of a protein complex that helps messenger RNA mature in the nucleus, U1-RNA is a major target of autoimmunity in lupus and related diseases.TLR3 is in a family of proteins that play a fundamental role recognizing pathogens and activating the innate immune system.
Using both human skin cells and a mouse model, the researchers found that UVB radiation fractures and tangles elements of a small non-coding nuclear RNA involved in pre-mRNA splicing. Irradiated cells release this altered RNA, provoking healthy, neighboring cells to start a process that results in an inflammatory response intended to remove sun-damaged cells. Humans see and feel the process as sunburn.
“The inflammatory response is important to start the process of healing after cell death,” Gallo said. “We also believe the inflammatory process may clean up cells with genetic damage before they can become cancer. Of course, this process is imperfect and with more UV exposure, there is more chance of cells becoming cancerous.”
The Nature Medicine study builds on findings from previous lupus studies that Greidinger and fellow VA co-author Laisel Martinez, M.S., a research scientist in Greidinger’s lab, conducted with initial funding from the Lupus Research Institute, and subsequent funding from the NIH and the VA. For this study, they contributed their expertise on the innate immune system and developed and provided the U1-RNA and key reagents for experiments that excluded other innate immune RNA-recognizing pathways as players in the sunburn process.
“This is a topic we are continuing to investigate,” Greidinger said. “The striking sensitivity of skin cells to RNA modified by UV light provides a new possible explanation for the red skin rashes experienced by lupus patients following sun exposure.”
University of Miami