Endogenous antisense RNA curbs CD39 expression in Crohn’s disease
Rasika Harshe, Anyan Xie, Marta Vuerich, Luíza Abrahão Frank, Barbora Gromová, Haohai Zhang, Rene’ J. Robles, Samiran Mukherjee, Eva Csizmadia, Efi Kokkotou, Adam S. Cheifetz, Alan C. Moss, Satya K. Kota, Simon C. Robson, Maria Serena Longhi
Abstract
CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine. CD39 is expressed by regulatory T (Treg)-cells, where it mediates immunosuppression, and by a subset of T-helper (Th) 17-cells, where it limits pathogenicity. CD39 is regulated via single-nucleotide-polymorphisms and upon activation of aryl-hydrocarbon-receptor and oxygen-mediated pathways. Here we report a mechanism of CD39 regulation that relies on the presence of an endogenous antisense RNA, transcribed from the 3'-end of the human CD39/ENTPD1 gene. CD39-specific antisense is increased in Treg and Th17-cells of Crohn's disease patients over controls. It largely localizes in the cell nucleus and regulates CD39 by interacting with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1. Antisense silencing results in CD39 upregulation in vitro and amelioration of disease activity in a trinitro-benzene-sulfonic-acid model of colitis in humanized NOD/scid/gamma mice. Inhibition/blockade of antisense might represent a therapeutic strategy to restore CD39 along with immunohomeostasis in Crohn's disease.