The Adenosine System at the Crossroads of Intestinal Inflammation and Neoplasia

Abstract

Adenosine is a purine nucleoside, resulting from the degradation of adenosine triphosphate (ATP). Under adverse conditions, including hypoxia, ischemia, inflammation, or cancer, the extracellular levels of adenosine increase significantly. Once released, adenosine activates cellular signaling pathways through the engagement of the four known G-protein-coupled receptors, adenosine A1 receptor subtype (A1), A2A, A2B, and A3. These receptors, expressed virtually on all immune cells, mitigate all aspects of immune/inflammatory responses. These immunosuppressive effects contribute to blunt the exuberant inflammatory responses, shielding cells, and tissues from an excessive immune response and immune-mediated damage. However, a prolonged persistence of increased adenosine concentrations can be deleterious, participating in the creation of an immunosuppressed niche, ideal for neoplasia onset and development. Based on this evidence, the present review has been conceived to provide a comprehensive and critical overview of the involvement of adenosine system in shaping the molecular mechanisms underlying the enteric chronic inflammation and in promoting the generation of an immunosuppressive niche useful for the colorectal tumorigenesis.

Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

“…The role of this receptor in the pathophysiology of inflammation is complex. Putten et al [ 60 ] pointed out that A3R-mediated signaling induced proinflammatory cytokines, while another study showed the protective effect of preventing excessive immune response and immune-mediated damage after A3R activation [ 61 ]. To date, research on downregulated ADORA3 and IPAH pathogenesis is insufficient, and the underlying mechanisms still need to be explored.…”

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

“…Adenosine downstream signaling is mediated via a set of P1 adenosine receptors (A1R, A2AR, A2BR, and A3R), which initiate G protein-coupled signaling and modulation of AC activity [ 97 , 118 ]. Adenosine receptors modulate cAMP production with differential effects, as A1R and A3R inhibit, whereas A2AR and A2BR enhance, cAMP production [ 95 , 119 ]. However, phosphorylation cascades downstream cAMP production may again converge into ERK1/2 activation and this may be stimulatory with all four receptors [ 95 ].…”

“…Adenosine receptors modulate cAMP production with differential effects, as A1R and A3R inhibit, whereas A2AR and A2BR enhance, cAMP production [ 95 , 119 ]. However, phosphorylation cascades downstream cAMP production may again converge into ERK1/2 activation and this may be stimulatory with all four receptors [ 95 ]. The biological effects of all receptors, with respect to cytokine release and inflammation, are uniformly anti-inflammatory, as it has been reported for the intestinal effects of adenosine signaling.…”

“…The biological effects of all receptors, with respect to cytokine release and inflammation, are uniformly anti-inflammatory, as it has been reported for the intestinal effects of adenosine signaling. The dark side of these effects, if chronically sustained, may be the support of immunosuppression and eventually the susceptibility to develop cancer [ 95 ]. Adenosine receptors are expressed in cells of the bone marrow and show effects on osteo- and adipogenesis [ 119 ].…”

Managing Obesity and Related Comorbidities: A Potential Pharmacological Target in the Adenosine System?

“…Over the years, several lines of evidence have outlined a critical role of the adenosine system in glucose homeostasis, inflammation, adipogenesis, insulin resistance and thermogenesis, thus suggesting an involvement of adenosine in the onset and progression of obesity ( Pardo et al, 2017 ; D’Antongiovanni et al, 2020b ). Indeed, the wide distribution of adenosine receptors (ARs) in tissues tightly involved in metabolism regulation leads to hypothesize the pharmacological modulation of adenosine pathways as a viable way to counteract obesity and related comorbidities ( Hasko et al, 2008 ; Antonioli et al, 2011 ; Kotanska et al, 2020 ).…”