Our organism swiftly responds to injuries or pathogen infections by mounting an inflammatory response. This fundamental biological mechanism is implemented with the help of cytokines and vascular endothelial cells which guide the immune cell trafficking through the vascular wall to the injured area. While inflammation may be a beneficial mechanism guarding our body against harmful invaders, its chronic activation may bear devastating and life-threatening consequences for our organism. Recently, inflammation has been classified as the strongest predictor for atherosclerotic heart disease risk [1]. Understanding how immune cells are recruited in the heart after acute myocardial infarction may lead to the development of novel therapeutics addressing the extremely high residual risk in these patients.
A recent study led by Dr. Aikaterini Gatsiou, an RNA biologist from the Newcastle University (UK), and Prof. Konstantinos Stellos, an academic cardiologist from the Heidelberg University (Germany), identified that a vascular endothelial RNA enzyme called adenosine deaminase acting on RNA -2 (ADAR2) orchestrates the immune cell trafficking and particularly the interleukin-6 (IL-6) trans-signaling-mediated inflammation in several preclinical ischemic disease models employed including acute myocardial infarction [2]. The international research team, comprised of researchers from elite research organizations spread across 8 countries (UK, Germany, USA, Italy, Japan, Greece, Sweden and China), uncovered the underlying mechanism how ADAR2 regulates immune cell trafficking using a prototypic convergence of advanced RNA biology methods, experimental disease models, and human tissue biopsies from patients with acute or chronic ischemic heart disease. Aided by a pioneering approach spanning from single nucleotide resolution up to organ level investigations, they defined that the vascular endothelial RNA editor, ADAR2, enzymatically changes the chemistry of certain adenosines in endothelial transcriptome reprogramming default molecular circuits and in this way promotes vascular endothelial inflammatory responses.
Owing to the fact that the observed endothelial RNA edits were related to a crucial component of the signaling cascade of the cytokine, IL-6, the researchers focused their investigations on the IL-6 pathway. Another surprising observation captured during this exploration was the remarkable effect of the selective inhibition of one of the two known IL-6 pathways, the IL-6-trans-signaling, in ischemia-induced inflammation. This finding revolutionize the views of the currently under advanced clinical testing global inhibitory drugs against both IL-6 pathways, recently reviewed in ref. [3] and suggest that human clinical trials shall consider examining selective IL-6-trans-signaling inhibitors for inflammation-related diseases. Considering also the recent advances in genome engineering technologies and particularly the RNA enzyme-assisted methods discussed in ref. [4], this study offers unrivalled insights into the development of precision medicine treatments targeting inflammatory diseases, including atherosclerosis.
The research work was mainly co-funded by the European Research Council, UK Research and Innovation (BBSRC), German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung; DZHK), Else Kröner-Fresenius-Stiftung (EKFS), and the German Research Foundation (DFG). The findings were published in the May issue of the journal "Immunity," the top-ranking scientific journal in immunology.
Figure 1. Scheme summarizing the study’s main findings. ADAR2 controls immune cell trafficking by altering the molecular reprogramming of endothelium in response to ischemia-induced IL-6 inflammation.
Figure 2. Artistic illustration of the study’s findings. The vascular endothelial cell RNA editor, ADAR2 (typewriter), modifies and downregulates RNA molecules (highlighted in gold) originally programmed to suppress the IL-6-trans-signaling immune responses and leukocyte (white) trafficking in postcapillary vessels (red) following an ischemic injury. Copyrights by Dr. Aikaterini Gatsiou.
Dr. Aikaterini Gatsiou
Biosciences Institute, Faculty of Medical Sciences,
Newcastle University, UK
Prof. Konstantinos Stellos
Department of Cardiovascular Research,
Mannheim Medical Faculty,
Heidelberg University, Germany
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