Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation

Aherne, Carol M.; Collins, Colm B.; Rapp, Caroline; Olli, Kristine E.; Perrenoud, Loni; Jedlicka, Paul; Bowser, Jessica L.; Mills, Tingting; Karmouty‐Quintana, Harry; Blackburn, Michael R.; Eltzschig, Holger K.

doi:10.1172/jci.insight.121521

Cited by 52 publications

(73 citation statements)

References 79 publications

(169 reference statements)

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“…The earliest link of extracellular adenosine to immunosuppression include studies on the anti-inflammatory activity of methotrexate (49) and seminal studies revealing A2AR signaling as essential in suppressing tissue-devastating inflammation (50). Extracellular adenosine protects tissues by dampening inflammation with myocardial injury (51)(52)(53), acute lung injury (54)(55)(56)(57)(58), intestinal ischemia-reperfusion injury (59)(60)(61), and inflammatory bowel disease (62)(63)(64)(65). Tumors exploit extracellular adenosine' to protect the cancer cells.…”

Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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“…For example, global A 2B AR deletion is protective against inflammatory damage induced by dextran-sulfate sodium (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), Salmonella typhimurium, and in IL-8-induced colitis [95]. However, recent studies on mice bearing A 2B AR conditional deletion on vascular endothelial or intestinal epithelial cells attribute the ability to reduce colonic inflammation only to A 2B ARs expressed by epithelial cells [97].…”

Section: Interesting Hints From the Long Considered Elusive Member Ofmentioning

confidence: 99%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

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“…7,20,21 Indeed, increased adenosine in extracellular space is known to dampen inflammation. 22 After initial increase, surface expression of CD73 reduced to the baseline level by day 14 (Figs. 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 13 (IL‐13) alters hypoxia‐associated genes and upregulates CD73

Khalil

Bernstein

Kulaga

et al. 2020

Int Forum Allergy Rhinol

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Background Interleukin 13 (IL‐13) is a pleiotropic cytokine that has been shown to be important in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and other type 2 inflammation–related diseases. Increased IL‐13 expression can elicit several pro‐inflammatory effects, including eosinophilia, and pathology such as increased mucus secretion. Polypogenesis in chronic rhinosinusitis (CRS) can be caused by hypoxia, which can also lead to hyperpermeability of airway epithelium and epithelium‐to‐mesenchymal translation through the upregulation of hypoxia‐associated genes, such as HIF1. Whether T‐helper 2 (Th2) inflammatory cytokines, such as IL‐13, can also induce sinonasal epithelial hypoxia‐associated genes is currently unknown. Methods Human air‐liquid interface (ALI) sinonasal epithelial cell cultures treated with recombinant IL‐13 were analyzed by real‐time polymerase chain reaction (PCR) and flow cytometry to determine the effect on epithelial cells. Results Whole tissue from CRSwNP subjects showed increased HIF1A gene expression. Treatment of fully differentiated human ALI cultures with IL‐13 resulted in a concurrent increase in HIF1A and ARNT messenger RNA (mRNA) expression. However, the level of EPAS1 expression was significantly reduced. IL‐13 also had a dose‐dependent response on the expression of HIF genes and the time course experiment showed peak expression of HIF1A and ARNT at 5 to 7 days poststimulation. Remarkably, CD73 surface expression also peaked at day 5 poststimulation. Conclusion Our data suggests that IL‐13 can induce hypoxia signaling pathway genes leading to surface expression of CD73, which has an anti‐inflammatory effect.

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Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation

Cited by 52 publications

References 79 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Adenosine Signaling in Autoimmune Disorders

Interleukin 13 (IL‐13) alters hypoxia‐associated genes and upregulates CD73

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