Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Key Points

  • Adenosine is a key endogenous molecule that is released from cells and regulates tissue function via activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. These receptors are abundantly expressed on the surface of immune cells as well as on endothelial, smooth muscle, epithelial cells, fibroblasts and cardiomyocytes.

  • Adenosine serves as an endogenous modulator of inflammatory and immune processes. Its release can be triggered from almost all cell types by ischaemia, hypoxia, inflammation and oxidative/nitrosative stress.

  • Adenosine receptors can be targeted for the treatment of various inflammatory diseases.

  • In asthma and chronic obstructive pulmonary disease, A2A receptor agonists prevent inflammatory cell infiltration into the lung. A2B receptor antagonists prevent mast-cell degranulation and the overproduction of pro-inflammatory mediators in the lung.

  • In ischaemia, A2A receptor agonists potently down-regulate inflammatory cell infiltration into tissues, production of deleterious free radicals and pro-inflammatory cytokines.

  • In arthritis, A2A receptor agonists have a wide range of anti-inflammatory effects in the inflamed joint. A3 receptor agonists decrease tumour necrosis factor-a production by monocytes and synoviocytes.

  • In sepsis, A1 receptor agonists can prevent inflammation-mediated organ injury in animal models. A2A receptor antagonists are beneficial in sepsis by boosting the eradication of bacteria.

  • In inflammatory bowel disease, A2A receptor agonists attenuate inflammatory cell sequestration in the gut and increase the activity of regulatory T cells thereby ameliorating the course of disease. A2B receptor antagonists prevent intestinal epithelial-cell-mediated inflammatory events and thereby prevent mucosal inflammation.

  • Topical administration of A2A receptor agonists increases the rate of wound healing in part by stimulating angiogenesis in the skin. Thus, A2A receptor agonists are good candidates for the treatment of diabetic foot ulcer.

  • In the clinic, A2A receptor agonists are being tested as therapeutic agents in wound healing and asthma. A2B receptor agonists have shown promise in clinical trials in patients with asthma and A3 receptor agonists improve symptoms in patients with rheumatoid arthritis.

Abstract

Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

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Figure 1: Representative adenosine receptor ligands.
Figure 2: Pattern-recognition receptor-mediated and A2A receptor-triggered pathways converge on CEBPβ to induce IL10 production by macrophages.
Figure 3: Mechanisms of TReg cell-mediated suppression of T-effector cells.
Figure 4: A2B receptor activation has broad pro-inflammatory actions by stimulating the pro-inflammatory functions of a variety of cell types that mediate asthma.
Figure 5: A2A receptor activation protects organs from ischaemia–reperfusion injury by widely inactivating the ischaemia–reperfusion-induced inflammatory response.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) Grant R01GM66189 and the Intramural Research Program of NIH, National Institute on Alcohol Abuse and Alcoholism.

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Correspondence to György Haskó.

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Competing interests

Joel Linden owns equity in Adenosine Therapeutics, LLC and holds patents related to adenosine.

Bruce Cronstein is the inventor on the following patents: use of A2A receptor agonists to promote wound healing and use of A2A receptor antagonists to inhibit fibrosis; use of A1 receptor antagonists to treat osteoporosis and other diseases of bone; use of A1 and A2B receptor antagonists to treat fatty liver; and use of A2A receptor agonists to prevent prosthesis loosening. Cronstein is consultant (within the past 2 years), all <£10,000, to companies: King Pharmaceutical, CanFite Biopharmaceuticals, Cypress Bioscience, Inc., Bristol-Myers Squibb, Cellzome, Tap Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Inc., Combinatorx, Kyowa Hakka, Hoffman-LaRoche, and Savient. He received stocks from CanFite Biopharmaceuticals for membership in their Scientific Advisory Board. He holds a grant from King Pharmaceuticals.

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DATABASES

IUPHAR Receptor Database

A1

A2A

A2B

A3

FURTHER INFORMATION

ClinicalTrials.gov

CV Therapeutics

King Pharmaceuticals

Glossary

Gi

An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that inhibits the activity of a downstream enzyme such as adenylyl cyclase.

Gs

An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that stimulates the activity of a downstream enzyme such as adenylyl cyclase.

Gq

An α-subunit of a heterotrimeric GTP-binding and GTP-hydrolysing protein (G protein) that stimulates the activity of a downstream enzyme such as phospholipase C.

NFATc1

NFATc1 is a member of the nuclear factor of activated T cells (NFAT) protein family, which are a family of transcription factors whose activation is controlled by calcineurin, a Ca2+-dependent phosphatase. They were originally identified in T cells as inducers of cytokine gene expression.

Pertussis toxin

A compound that inhibits the guanine nucleotide binding proteins Gi and Go via ADP ribosylation.

Macrophage

One of the main types of professional phagocytes. Macrophages are long-lived and detrimental for many microbial pathogens. Intracellular bacteria can survive within the macrophages. They can mediate antibody-dependent cellular cytotoxicity through phagocytosis.

Adenosine deaminase

Adenosine deaminase irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the removal of an amino group.

Alloimmune reaction

Alloimmunity is an immune reaction against non-self material from the same species.

Dendritic cell

These professional antigen-presenting cells are increasingly recognized as having crucial immunoregulatory functions. They are found in various tissues where they take up antigens, process them, migrate to the lymph nodes and present the antigens to T cells.

CD4+ cells

Cells expressing the CD4+ glycoprotein that recognises major histocompatibility class II molecules.

TH1 and TH2 cells

The TH1/TH2 hypothesis came to prominence in the late 1980s, indicating that mouse T-helper (TH) cells broadly express differing cytokine profiles. T helper 1 (TH1) cells secrete interferon-γ and tumour necrosis factor-α. TH2 cells secrete interleukin 4 (IL4), IL5 and IL13. In addition, TH3 and regulatory CD4+CD25+ T cells exist that produce transforming growth factor-a and IL10, respectively.

Mast cell

A bone marrow-derived cell that is present in various tissues; they are important contributors to allergic disease and possibly arthritis. They are granular cells that bear Fc receptors for immunoglobulin E (IgE), which, when crosslinked by IgE and antigen, causes degranulation and release of mediators such as histamine, leukotrienes and PGD2.

Antigenic stimulation

When the body's immune system responds to a foreign substance.

Inverse agonists

Inverse agonists reverse constitutive receptor activity, and are proposed to show selectively higher affinity for the inactive versus the active conformation of the receptor. In the absence of constitutive activity, inverse agonists function as competitive antagonists.

Lymphocyte

White blood cells of lymphoid origin that function as part of the immune system.

TC1 and TC2 CD8+ cells

CD8+ T cells have been subdivided into CD8+ T cells secreting a TH1-like cytokine pattern, which are defined as TC1 (T cytotoxic type 1) cells, versus CD8+ T cells secreting a TH2-like pattern (TC2 cells).

Natural killer (NK) cells

A lymphocyte subset that is part of the innate immune response and is able to recognize virus-infected or transformed cells that lack major histocompatibility class I expression. In contrast to T cells, NK cells do not require activation but are able to immediately kill these cells.

Regulatory T (TReg) cells

TReg cells are a CD4+ T-cell subset that are characterized by the expression of CD25 (interleukin 2 receptor-(IL2R) subunit) and FOXP3. TReg cells are powerful suppressors of adaptive immune responses.

MHC molecules

Originally named because they function as transplantation antigens. MHC molecules have a crucial role in antigen presentation, and serve as accessory binding proteins for T-helper and T-killer cells.

Invariant NKT (iNKT) cells

A rare subset of lymphocytes that expresses an invariant T-cell receptor that recognizes certain glycolipids when bound to the major histocompatibility complex class I-like molecule, CD1d. Through secretion of cytokines they are powerful modulators of adaptive immune responses.

Cecal ligation and puncture

An experimental model of polymicrobial sepsis that is generally considered more relevant to the human disease than rodents injected with bacterial lipopolysaccharide (endotoxin).

Angiogenesis

The growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development but it also a fundamental process required for the growth of tumours.

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Haskó, G., Linden, J., Cronstein, B. et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7, 759–770 (2008). https://doi.org/10.1038/nrd2638

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