Regulation of Leukocyte Function by Adenosine Receptors

Abstract

The immune system responds to cues in the microenvironment to make acute and chronic adaptations in response to inflammation and injury. Locally produced purine nucleotides and adenosine provide receptor-mediated signaling to all bone-marrow derived cells of the immune system to modulate their responses. This review summarizes recent advances in our understanding of the effects of adenosine signaling through G protein-coupled adenosine receptors on cells of the immune system. Adenosine A2A receptors (A2ARs) have a generally suppressive effect on the activation of immune cells. Moreover, their transcription is strongly induced by signals that activate macrophages or dendritic cells through toll-like receptors, or T cells through T cell receptors. A2AR induction is responsible for producing a gradual dissipation of inflammatory responses. A2AR activation is particularly effective in limiting the activation of invariant NKT (iNKT) cells that play a central role in acute reperfusion injury. A2A agonists have clinical promise for the treatment of vaso-occlusive tissue injury. Blockade of A2A receptors may be useful to enhance immune-mediated killing of cancer cells. A2BR expression also is transcriptionally regulated by hypoxia, cytokines, and oxygen radicals. Acute A2BR activation attenuates the production of proinflammatory cytokines from macrophages, but sustained activation facilitates macrophage and dendritic cell remodeling and the production of acute phase proteins and angiogenic factors that may participate in evoking insulin resistance and tissue fibrosis. A2BR activation also influences macrophage and neutrophil function by influencing expression of the anti-inflammatory netrin receptor, UNC5B. The therapeutic significance of adenosine-mediated effects on the immune system is discussed.

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“…Rather, it seems plausible that adenosine may exert cardioprotection by stimulation of adenosine A2a receptors on neutrophils and macrophages 59, 60, 61. While a number of adenosine receptor isoforms exist, stimulation of the adenosine A2a receptor pathway may predominate when biological concentrations of adenosine increase 62. Activation of the adenosine A2a‐receptor signaling pathway is implicated in phosphorylation of cyclic‐AMP responsive element‐binding protein, which in turn inhibits nuclear factor‐κβ through competitive binding at DNA transcriptional promoter sites 63.…”

Adenosine A1Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms

“…(C) Retinal pathologic angiogenesis at P17 was observed by using hematoxylin and eosin staining (n ¼ 7 cytokines such as interleukin-1b (IL-1b) and tumor necrosis factor-a, which lead to a delayed (~24 hours), marked, and sustained increase in adenosine receptor (particularly A 2A R and the A 2B R) expression in tissues and inflammatory cells. [43][44][45] Locally increased adenosine levels and adenosine receptor signaling might represent a local ''find-me'' signal and service a unique ''purinergic chemotaxis'' for a local resolution to pathologic conditions (as revealed by genetic KO studies). 10 Thus, the surge of adenosine level and the induction of adenosine receptors in the hypoxic phase of OIR 11 may constitute a negative feedback and defense mechanism countering such proangiogenic states triggered by hypoxia and HIF-1a-mediated expression of VEGF in retina.…”

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…2 Conversely, the ATP-metabolite adenosine has extensive immunosuppressive effects 3,4 via binding to a range of adenosine-receptors present on most immune cells. 5 ATP conversion into ADP and 5 0 -AMP is catalyzed by CD39, whereas AMP is hydrolyzed by CD73 to adenosine. In the tumor microenvironment, the CD39/CD73/adenosine axis contributes not only to immunosuppression but also directly supports tumor growth, differentiation, metastasis and angiogenesis.…”