The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation

Gatsiou, Aikaterini and Tual-Chalot, Simon and Napoli, Matteo and Ortega-Gomez, Almudena and Regen, Tommy and Badolia, Rachit and Cesarini, Valeriana and Garcia-Gonzalez, Claudia and Chevre, Raphael and Ciliberti, Giorgia and Silvestre-Roig, Carlos and Martini, Maurizio and Hoffmann, Jedrzej and Hamouche, Rana and Visker, Joseph R and Diakos, Nikolaos and Wietelmann, Astrid and Silvestris, Domenico Alessandro and Georgiopoulos, Georgios and Moshfegh, Ali and Schneider, Andre and Chen, Wei and Guenther, Stefan and Backs, Johannes and Kwak, Shin and Selzman, Craig H and Stamatelopoulos, Kimon and Rose-John, Stefan and Trautwein, Christian and Spyridopoulos, Ioakim and Braun, Thomas and Waisman, Ari and Gallo, Angela and Drakos, Stavros G and Dimmeler, Stefanie and Sperandio, Markus and Soehnlein, Oliver and Stellos, Konstantinos (2023) The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation. Immunity, 56 (5). 979-997.e11. ISSN 1074-7613

Abstract

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.