Written by Charlotte Harrison, Science Writer
A paper published in the journal Immunity has identified a new role for the RNA editing enzyme ADAR2 in the trafficking of immune cells.
ADAR2 is an adenosine deaminase that converts adenosine to inosine within RNA. To date, its main physiological function is ascribed to exonic RNA editing of the neuronal glutamate receptor to control neuronal homeostasis.
In the new research, researchers showed that ADAR2 controls endothelial interleukin (IL)-6 signalling and recruitment of immune cells to vascular endothelium. The findings increase our understanding of the pathogenesis of ischemic disease and hint that ADAR2 might be a future therapeutic target for disorders that involve IL6 signalling.
Controlling IL-6 signalling
Given that vascular tissue is one of the most highly edited tissues in the body, the authors used this tissue type for the focus of their studies on ADAR2. Gene silencing studies in endothelial cells showed that ADAR2 controls IL-6 signalling in this cell type.
The authors then used three mouse genetic models (IL6 loss, global ADAR2 loss, vascular endothelial cell-restricted ADAR2 loss) to show that ADAR2 was not involved in immune and vascular system homeostasis. However, ADAR2 did play an important role in IL-6 signalling- and ischemia-induced immune cell trafficking.
ADAR2 in humans
In patients with acute heart disease,serum IL-6 levels increased rapidly after a heart attack, and a higher IL-6 increase was a predictor of more severe disease. Histological analysis of the heart tissue showed ADAR2 levels correlated with the number of infiltrated immune cells.
Similar increases in IL6 were observed in patients with chronic heart disease, and here the authors were able to show that cardiac levels of IL6 receptor-α protein also increased.
Moreover, several findings from human samples were replicated in a murine model of acute ischaemic heart disease. The researchers showed that immune-cell infiltration, the expression of cellular adhesion molecules, and the extent of tissue injury were reduced in ADAR2-deficient mice.
Finally, the authors conducted unbiased transcriptome-wide analyses and miR-sequencing to show that ADAR2 controls the expression of a group of miRNAs that target the 3′ UTR of the IL6 gene.
The next steps of the work will be to determine if pharmacological manipulation of ADAR2 inhibits IL-6 signalling and excessive leukocyte infiltration in disease models. Such an approach might offer a tissue-specific alternative to targeting IL6 directly.