Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

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.

Figure 1. Representative adenosine receptor ligands

These ligands are the most widely used adenosine receptor agonists and antagonists in in vitro and in vivo studies assessing the function of adenosine receptors. IB-MECA (CF101) is currently undergoing testing in clinical trials for the treatment of rheumatoid arthritis.

Figure 2. Pattern-recognition receptor-mediated and A_2A receptor-triggered pathways converge on CEBPβ to induce IL10 production by macrophages

A_2A receptor activation increases intracellular cyclic AMP (cAMP) levels resulting in increased protein kinase A (PKA) activation. PKA phosphorylates cAMP responsive element binding protein (CREB), which causes an increase in its transactivating potential leading to the transcription of the CEBPβ gene. CEBPβ protein binds to the IL10 gene promoter, which triggers IL10 transcription and subsequently leads to the release of IL10. Components of Escherichia coli trigger activation of pattern-recognition receptors (PRRs) and bring about increased activation of CEBPβ.

Figure 3. Mechanisms of T_Reg cell-mediated suppression of T-effector cells

Regulatory T (T_Reg) cells produce adenosine following sequential degradation of ATP/ADP via CD39 (ENTPD1; ectonucleoside triphosphate diphosphohydrolase 1) and CD73 (ecto-5′-nucleotidase) (a). Adenosine activates A_2A receptors on T-effector cells to inhibit T-cell receptor (TCR)-mediated signalling by preventing ZAP70 phosphorylation and activation of the transcription factor activator protein 1 (AP1) (b). This decreased TCR signalling leads to decreased interleukin 2 (IL2) production and CD25 expression resulting in decreased T effector cell proliferation. In addition, the development of both T helper 1 (T_H1) and T_H2 cells, as well as the generation of T_H17 lymphocytes is inhibited following A_2A receptor stimulation. A_2A receptor stimulation on T-effector cells increases expression of negative co-stimulatory molecules such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death 1 (PD1). A_2A receptor stimulation on T_Reg cells augments FOXP3 expression in these cells.

Figure 4. A_2B receptor activation has broad pro-inflammatory actions by stimulating the pro-inflammatory functions of a variety of cell types that mediate asthma

A_2B receptor activation increases interleukin 6 (IL6) production by pulmonary fibroblasts, which in turn leads to increased generation of myofibroblasts, which are capable of depositing extracellular matrix. A_2B receptor activation promotes the production of pro-inflammatory factors by mast cells and stimulates mast-cell degranulation. Increased IL4 production following mast cell A_2B receptor activation leads to increased immunoglobulin E (IgE) production by B cells. bFGF, basic fibroblast growth factor; MCP1, monocyte chemoattractant protein 1; VEGF, vascular endothelial growth factor.

Figure 5. A_2A receptor activation protects organs from ischaemia–reperfusion injury by widely inactivating the ischaemia–reperfusion-induced inflammatory response

A_2A receptor activation reduces ischaemia–reperfusion-induced rolling, adhesion and transmigration of various inflammatory cells, including natural killer T (NKT) cells, lymphocytes and neutrophils. A_2A receptor stimulation also limits inflammatory cytokine and chemokine production, superoxide release and interferon-γ (IFN-γ) secretion by activated immune cells. NO, nitric oxide; TNF-α, tumour-necrosis factor-α.