Adenosine-mediated immune responses in inflammatory bowel disease

Abstract

Extracellular ATP and its derivates mediate a signaling pathway that might be pharmacologically targeted to treat inflammatory conditions. Extracellular adenosine, the product of ATP hydrolysis by ectonucleotidase enzymes, plays a key role in halting inflammation while promoting immune tolerance. The rate-limiting ectoenzyme ENTPD1/CD39 and the ecto-5'-nucleotidase/CD73 are the prototype members of the ectonucleotidase family, being responsible for ATP degradation into immunosuppressive adenosine. The biological effects of adenosine are mediated via adenosine receptors, a family of G protein-coupled receptors largely expressed on immune cells where they modulate innate and adaptive immune responses. Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract, associated with substantial morbidity and often refractory to currently available medications. IBD is linked to altered interactions between the gut microbiota and the immune system in genetically predisposed individuals. A wealth of studies conducted in patients and animal models highlighted the role of various adenosine receptors in the modulation of chronic inflammatory diseases like IBD. In this review, we will discuss the most recent findings on adenosine-mediated immune responses in different cell types, with a focus on IBD and its most common manifestations, Crohn's disease and ulcerative colitis.

Keywords: ATP; adenosine; adenosine receptors; inflammation; inflammatory bowel disease.

FIGURE 1

Adenosine receptor signaling in different immune cell types. (A) Adenosine mediates immature human plasmacytoid dendritic cells (PDCs) recruitment to inflammatory sites, via A₁ receptor (A₁R) signaling. At the infection site, PDCs undergo maturation by decreasing A₁R expression, in favor of A_2AR, which limits pro-inflammatory cytokine release. (B) Human and murine Tregs express CD39 that initiates ATP/ADP hydrolysis to ultimately produce adenosine. Expression of A_2AR by Tregs enables adenosine to act in an autocrine manner that might favor the maintenance of the Treg-cell pool. (C) In mouse peritoneal macrophages, adenosine suppresses LPS-induced IL-1β release, ROS, and nitrite production. A_2BR stimulation boosts IL-10 production and suppresses pro-inflammatory responses (D) A₃R can activate human mast cells independently of IgE and triggers upregulation of growth factors, cytokines, and chemokines. The effect of adenosine on human mast cells also depends on A_2BR, which promotes release of Th2 cytokines like IL-4 and IL-13 to induce IgE synthesis in B lymphocytes.

FIGURE 2

Adenosine-related pathways in IBD. Blood and lamina propria of Crohn’s disease patients are characterized by reduced frequencies of suppressive CD39⁺ Th17-cells (supTh17), an immunoregulatory Th17-cell population that is impaired in IBD. In colon epithelial cells from UC patients, A₃R is downregulated, and its expression levels inversely correlate with mir-206. Increase in A_2BR levels during intestinal IRI and acute hypoxia has been implicated in reduced transepithelial resistance and increased epithelial damage. In the colonic mucosa of UC patients, A_2AR is post-transcriptionally downregulated by miR-16, this limiting A_2AR anti-inflammatory effects.