Immune cells are directed to regions of tissue damage via RNA editing

Immune cells are directed to regions of tissue damage via RNA editing

By investigating vascular disorders, a group of international researchers led by Heidelberg University, Medical Faculty Mannheim, and Newcastle University (Great Britain) have succeeded in deciphering a brand-new immune cell trafficking mechanism. Surprisingly, an RNA editing system (ADAR2) in the endothelial cells that line the blood arteries is responsible for fine-tuning this essential immune defence mechanism. This information may lead to the development of novel treatment strategies for a wide range of inflammatory illnesses.

Immune cells are directed to regions of tissue damage via RNA editing.

Chemical signals known as cytokines induce immune cells to leave the circulation and go through the blood vessel wall to the location of the damage or infection when our body sustains an injury or becomes infected by pathogens. The movement of immunological cells through the body is crucial for the body's defence mechanisms.

Nevertheless, if this process continues over time, it can result in lingering tissue inflammation and organ damage, which would subsequently promote the establishment of chronic inflammatory illnesses including cancer and heart disease. Immune cell trafficking is therefore a key factor that may be used to modulate inflammatory processes and is now being researched as a potential pharmaceutical target for the treatment of a number of illnesses.

Using ischemia disorders as an illustration, the multinational study team conducted their research. Our body's inability to get enough oxygen to the damaged tissue if we have an ischemia condition causes cytokines to be produced. Heart failure is the most typical result of ischemic chronic heart disease.

"A key mechanism behind ischemic heart disease is chronic inflammation. After a heart attack, a person is more likely to experience consequences including heart failure, a second attack, or other health issues. Understanding the recruitment of immune cells into the heart following an acute heart attack or in chronic ischemic heart disease could help us create novel therapies that may lower this risk, known as residual risk, says Professor Konstantinos Stellos.

He performed the majority of the work at Newcastle University in the UK alongside the study's lead author, Dr. Aikaterini Gatsiou, an RNA biologist. He carried on his work when he moved to Heidelberg University's Mannheim Medical Faculty in 2021 to take on the Chairmanship of the Department of Cardiovascular Research.

An RNA enzyme has been found to coordinate the inflammatory response in the heart or in other ischemic muscle tissues, making it a potentially effective treatment for a variety of inflammatory illnesses. RNA editing is the act of changing one RNA alphabet letter, adenosine, to another letter, inosine, at specified places in RNA. ADAR2 (Adenosine Deaminase Acting on RNA-2) accurately catalyses this transition.

The precise method by which RNA editing regulates immune cell trafficking in ischemia disorders was determined by the researchers at single nucleotide resolution up to organ level.

"We think that the propensity of basic research studies to rely scientific discoveries on a single level of analysis is a substantial barrier to the quick development of novel medicines. Being multilayered creatures, it is best to study and evaluate all mechanistic levels utilising human and murine primary cells, experimental illness models, and human biopsies in order to find novel pathways that may be pharmacologically addressed. This is precisely the goal we set while creating this examination, which was carried out with the assistance of numerous professionals from other research disciplines who made substantial contributions to this study, said Professor Stellos and Dr. Gatsiou.

In addition to being a potential therapeutic target in and of itself, the RNA enzyme ADAR2's activity may also be exploited as a complement to genome editing techniques. Scientists may now selectively alter an organism's DNA to treat ailments using the CRISPR/Cas9 gene scissors. The method does, however, carry hazards since it causes irreversible DNA modifications.

"Using RNA editing is a more promising strategy for the creation of treatments for inflammatory illnesses including cancer, heart failure, and autoimmune disorders. Due to RNA's limited lifespan, RNA editing doesn't affect DNA, is very selective, and has a dose-dependent impact. According to Dr. Aikaterini Gatsiou, our study offers an integrated foundation for such initiatives. Professor Stellos continues, "Interestingly, multiple research teams are focusing on the utilisation of human ADAR enzymes as programmable RNA editing machines.

The results of this study have the potential to revolutionise the way numerous diseases are treated because inflammation is a common mechanism in many maladies. Today, Immunity released the results online.