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.
Highlights
CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine
CD39 regulates immune homeostasis by hydrolyzing adenosine triphosphate (ATP) and adenosine diphosphate into adenosine monophosphate (AMP) that is subsequently converted into adenosine by CD73, the ectoenzyme that works in tandem with CD391–3
We have previously demonstrated that human CD39 is regulated at the genetic level via SNPs in the promoter region of the gene that are associated with altered CD39 mRNA expression[9] and at the transcriptional level upon engagement of stimulatory or inhibitory pathways governed by aryl hydrocarbon receptor (AhR) and HIF-1α/hypoxia[8,20,27]
Summary
CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine. 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-nuclearribonucleoprotein-A1. CD39 is expressed on various immune cells, including regulatory T (Treg) cells, where it mediates suppressive function[4,5,6], and by a subset of effector T helper type 17 (Th17) cells, where it marks the acquisition of regulatory properties and limits pathogenic potential[7,8]. CD39 levels and function are decreased in both Treg and Th17 cells derived from the peripheral blood and lamina propria (LP) of Crohn’s disease patients[7,8,10], this being associated with defective Treg function and impaired Th17 cell ability to undergo immunoregulation and subsequent perpetuation of pathogenic potential. We recently found that protracted hypoxia, which is associated with chronic inflammatory statuses, interferes with CD39 levels by inhibiting AhR signaling in Crohn’s derived Th17 cells[20]
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