The Hypoxia–Adenosine Link during Intestinal Inflammation

Bowser, Jessica L.; Phan, Luan H.; Eltzschig, Holger K.

doi:10.4049/jimmunol.1701414

Cited by 52 publications

(40 citation statements)

References 185 publications

(242 reference statements)

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“…With tissue damage, inflammation, and hypoxic stress, ATP is released from stressed, necrotic, and/or apoptotic cells and is hydrolyzed stepwise by ectonucleoside triphosphate diphosphohydrolase-1 (CD39), converting ATP to AMP, and CD73, converting AMP to extracellular adenosine (Figure 1). ATP's activation of ATP receptors promotes inflammation, whereas subsequent breakdown of ATP to extracellular adenosine and activation of adenosine receptors dampens inflammation (Figure 1) (45)(46)(47). Extracellular adenosine signals though four adenosine receptors: A1R, A2AR, A2BR, and A3R (48).…”

Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 99%

“…In these preclinical studies, extracellular adenosine levels and CD39, CD73, A2AR, and A2BR gene expression decreases and coincides with increased antitumor immunity (102,108). Hypoxiainducible factors (HIFs) are strongly linked to increasing CD73 (109), A2AR (110), and A2BR (111) gene expression and collaborates to increase extracellular adenosine/adenosine receptor signaling for dampening inflammation (46,47). Interestingly, recent studies show tumor cells can reprogram NK cells to gain immunosuppressive functions [e.g., increase IL-10 and transforming growth factor-β (TGF-β) production via signal transducer and activator of transcription 3 (STAT3) transcriptional activity, suppressing IFN-γ production] (112).…”

Section: Natural Killer Cellsmentioning

confidence: 99%

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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%

Section: Natural Killer Cellsmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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Section: Functional Roles Of Myeloid Mir‐223 During Inflammatory Disementioning

confidence: 99%

“…IBD, including Crohn's disease and ulcerative colitis, are characterized by disrupted epithelial barrier function, increased bacterial translocation and dysregulated immunological environment in the gut. [75][76][77][78][79][80][81][82][83] Adaptive immunity, Th17 responses especially, plays a crucial role in the propagation of inflammation during IBD. 84,85 On the other hand, dendritic cell (DC) and macrophages are also crucial in the maintenance of intestinal immune homeostasis.…”

Section: Mir-223 In Inflammatory Bowel Diseasesmentioning

confidence: 99%

MicroRNA miR-223 as regulator of innate immunity

Yuan

Berg

Lee

et al. 2018

Journal of Leukocyte Biology

134

105

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MicroRNAs were discovered more than 2 decades ago and have profound impact on diverse biological processes. Specific microRNAs have important roles in modulating the innate immune response and their dysregulation has been demonstrated to contribute to inflammatory diseases. MiR-223 in particular, is very highly expressed and tightly regulated in hematopoietic cells. It functions as key modulator for the differentiation and activation of myeloid cells. The central role of miR-223 in myeloid cells, especially neutrophil and macrophage differentiation and activation has been studied extensively. MiR-223 contributes to myeloid differentiation by enhancing granulopoiesis while inhibiting macrophage differentiation. Uncontrolled myeloid activation has detrimental consequences in inflammatory disease. MiR-223 serves as a negative feedback mechanism controlling excessive innate immune responses in the maintenance of myeloid cell homeostasis. This review summarizes several topics covering the function of miR-223 in myeloid differentiation, neutrophil and macrophage functions, as well as in inflammatory diseases including acute respiratory distress syndrome and inflammatory bowel disease. In addition, nonmyeloid functions of miR-223 are also discussed in this review. Therapeutic enhancement of miR-223 to dampen inflammatory targets is also highlighted as potential treatment to control excessive innate immune responses during mucosal inflammation.

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“…IRI by definition results in profound tissue hypoxia, which causes the stabilization and activation of hypoxia‐inducible factors (HIFs), a group of transcription factors that regulate not only general inflammatory transcriptional programs, but are also a key mediator of nucleotide receptor and transporter transcription. In the context of organ transplantation, the action of HIFs may serve as a central modulator of the outcomes of nucleotide signaling (see reviews by Bowser et al and Le et al for a more thorough examination of the role of HIFs in adenosine nucleotide signaling). For example, A2BR‐dependent stabilization of the rhythm protein Per2 has been shown to be required for the full protective effect of ischemic preconditioning in myocardial infarction models in a HIF‐dependent manner .…”

Section: Targeting Atp In Iri and Graft Preservationmentioning

confidence: 99%

Extracellular nucleotide signaling in solid organ transplantation

Yeudall

Leitinger

Laubach

2020

American Journal of Transplantation

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The role of extracellular purine nucleotides, including adenosine triphosphate (ATP) and adenosine, as modulators of posttransplantation outcome and ischemia‐reperfusion injury is becoming increasingly evident. Upon pathological release of ATP, binding and activation of P2 purinergic surface receptors promote tissue injury and inflammation, while the expression and activation of P1 receptors for adenosine have been shown to attenuate inflammation and limit ischemia‐induced damage, which are central to the viability and long‐term success of allografts. Here we review the current state of the transplant field with respect to the role of extracellular nucleotide signaling, with a focus on the sources and functions of extracellular ATP. The connection between ischemia reperfusion, purinergic signaling, and graft preservation, as well as the role of ATP and adenosine as driving factors in the promotion and suppression of posttransplant inflammation and allograft rejection, are discussed. We also examine novel therapeutic approaches that take advantage of the ischemia‐reperfusion‐responsive and immunomodulatory roles for purinergic signaling with the goal of enhancing graft viability, attenuating posttransplant inflammation, and minimizing complications including rejection, graft failure, and associated comorbidities.

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The Hypoxia–Adenosine Link during Intestinal Inflammation

Cited by 52 publications

References 185 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

MicroRNA miR-223 as regulator of innate immunity

Extracellular nucleotide signaling in solid organ transplantation

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