Trends in Immunology
ReviewA2B adenosine receptors in immunity and inflammation
Introduction
Adenosine is a primordial regulator of multiple physiological processes and its modulatory actions have been demonstrated in organisms as diverse as Drosophila[1], the common mussel Mytilus edulis[2], the protozoan Leishmania mexicana[3] and mammals such as Mus musculus4, 5 and humans 4, 5. Adenosine is an extracellular purine nucleoside signaling molecule, which governs cell and tissue function both in health and disease. Adenosine is formed after the degradation of its precursor, adenosine 5′ triphosphate (ATP), a process which can take place both extra- and intracellularly. ATP, a predominantly intracellular molecule, is released from the cell after stressful and injurious events, and is degraded to adenosine via a cascade of ectonucleotidases, including CD39 (nucleoside triphosphate diphosphorylase [NTPDase]) and CD73 (5′-ectonucleotidase [Ecto5′NTase]) [6]. Intracellular ATP metabolized to adenosine is exported from the cell through nucleoside transporters [7]. Cells of the immune system including neutrophils, mast cells, endothelial cells, regulatory T cells and platelets have been appreciated as the most prodigious sources of extracellular adenosine [8]. In addition to serving as a source for adenosine release, immune cells are also among the most widely studied cell types targeted by the regulatory influences of adenosine [9]. Adenosine imparts its immune regulatory actions by binding to and activating four G protein-coupled cell surface receptors, A1, A2A, A2B and A37, 9. Although A1, A2A and A3 receptors are high-affinity receptors that are activated by physiological extracellular adenosine concentrations in the submicromolar range, A2B receptors are activated by micromolar levels of adenosine, concentrations that are achieved in tissues that experience ischemia, trauma, inflammation or other types of stressful insults. This low affinity of A2B receptors for the endogenous ligand adenosine and other selective agonists had, until a few years ago, impeded exploration of the role of this receptor subtype in regulating immune function. The recent availability of sophisticated pharmacological and molecular tools has however dramatically invigorated research on the role of A2B receptors in regulating immunity. Here, we review recent advances in understanding the role of A2B receptors in modulating inflammation and immunity, which might provide a basis for the utilization of these receptors as pharmacological targets in treating immune system dysfunction and inflammation.
Section snippets
Distribution of A2B receptors
A new mouse model incorporating targeted deletion of A2B receptors and replacement of exon 1 with a reporter gene has allowed in vivo determination of which cell types and tissues express A2B receptors in the mouse [10]. A2B receptors have been found in all tested organs, including spleen, lung, colon and kidney, and in all of these organs the primary site of expression was the vasculature. Smooth muscle cells, endothelial cells and macrophages exhibit a high level of expression [10], and A2B
Regulation of A2B receptor expression
The signaling capacity of A2B receptors depends on several factors, which include A2B receptor density on the cell surface and A2B receptor coupling to downstream intracellular signaling pathways. A2B receptor expression on the cell surface is a highly regulated and dynamic process, which is influenced by metabolic, inflammatory and hormonal clues from the environment and by adenosine itself. Hypoxia is an important stimulus for the upregulation of A2B receptor expression and it has been shown
Signaling pathways of A2B receptors
A2B receptors couple to a variety of intracellular signaling pathways, the best studied of which are Gs-mediated signaling to PKA, resulting in increased cAMP levels and Gq-mediated activation of phospholipase C (PLC) leading to increased protein kinase C (PKC) activation and elevations in intracellular Ca2+ levels [29]. These two pathways are often activated simultaneously, which enables additional levels of fine-tuning of cellular processes. In addition to these two most important signaling
The pharmacology of A2B receptors
The pharmacological characterization of A2B receptors has lagged behind that of A1, A2A and A3 receptors because until recently, potent and selective A2B receptor ligands had not been available. NECA (5′-N-ethylcarboxamidoadenosine) is the most widely used A2B receptor agonist; however, it is neither selective nor potent. Nevertheless, in those rare cellular systems in which A2B receptors are the only adenosine receptors expressed, a role for A2B receptors in regulating a particular response
Mast cells
Mast cell activation has long been recognized as a crucial factor in the pathophysiology of asthma and other allergic diseases [30]. Mast cells are also increasingly appreciated as a crucial cell type in initiating and maintaining inflammatory and immune responses, owing to their ability to rapidly release biogenic amines, proinflammatory lipid molecules and cytokines [31]. Adenosine receptors on mast cells have become of considerable interest as therapeutic targets for asthma, based on the
Asthma and chronic obstructive pulmonary disease
There is an increasing body of evidence documenting the proinflammatory effects of A2B receptor activation in both rodent and human asthma and chronic obstructive pulmonary disease (COPD), which indicates that A2B receptor antagonists might be of therapeutic value in preventing disease progression in asthma and COPD. This is borne out by recent in vivo evidence [61] showing that selective antagonism of adenosine A2B receptors leads to inhibition of airway inflammation and airway reactivity
Conclusions and perspectives
Research into the role of A2B receptors in regulating immunity and inflammation has gained momentum with the recent availability of KO mouse models and selective receptor ligands. Based on the new information acquired through this research it has become clear that A2B receptors represent potential targets for manipulation in the treatment of immune-mediated and inflammatory diseases. A2B receptors can be advantageous targets for pharmacological intervention because their expression is normally
Acknowledgements
This work was supported by the National Institutes of Health Grant R01 GM66189 and the Intramural Research Program of NIH, National Institute on Alcohol Abuse and Alcoholism, as well as Hungarian Research Fund OTKA (K73110) and Marie Curie Grant PIRG02-GA-2007–224767.
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