Adenosine receptors modulation of inflammatory cells: the foam cells history.

Adenosine is an endogenous purine nucleoside that is constitutively present at low levels outside the cells but might dramatically increase its concentrations following metabolic stress conditions like those induced by hypoxia or ischaemia. After its release adenosine induces its biological effects through the interaction with four cell surface receptors classified by molecular, biochemical and pharmacological data into four subtypes: A1, A2A, A2B and A3. Adenosine through the interaction with A2 and A3 receptors plays a crucial role in inflammation and in the regulation of immune cells. A2A receptors, proposed as “natural” brakes of inflammation, appear to represent a promising pharmacological target to treat a wide variety of diseases characterized by a strong immunoinflammatory component. On the other hand, it may be advantageous in some circumstances to enhance certain aspects of inflammation in order to eliminate the causative agent, as in the case of cancer. In fact, it has to be remarked that tumour defence mechanisms are akin to inflammatory processes. Solid tumours, due to their abnormal vasculature, are often hypoxic and show increased levels of adenosine that may be an important mediator of tumour-associated immunosuppression. It is likely that killer T cells that may be recruited against cancer cells fail to act in an effective manner due to the high level of adenosine in the tumour microenvironment. Because several of these immunosuppressive effects have been attributed to the stimulation of A3 and A2A receptors, expressed on the surface of T cells, adenosine antagonists of these subtypes may be potentially useful in the immunotherapy of cancer. The interest in the elucidation of A3 adenosine receptor involvement in inflammation is evident from the large amount of experimental work carried out in peripheral blood cells of the immune system and in a variety of inflammatory conditions. A3 adenosine receptor subtype play a complex role as both pro and anti-inflammatory effects depending not only on the cell types investigated but also on the model of inflammation used and the species considered. In this study we discuss developments in our understanding of the role of adenosine A3 receptor activation in the function of the different types of cells of the immune system including neutrophils, eosinophils, lymphocytes, monocytes, macrophages and dendritic cells. Then we focused our attention on the role of adenosine in atherosclerosis, a chronic inflammatory disease of the arteries, characterized by an hypoxic region with an high concentration of adenosine and a large number of foam cells. Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and foam cells development. As hypoxia induces HIF-1α stabilization and adenosine accumulation, we investigated whether this nucleoside regulates HIF-1α in FC. Adenosine, under hypoxia, stimulates HIF-1α accumulation by activating all adenosine receptors, while it has only a slight effect in normoxia. HIF-1α modulation involved extracellular signal-regulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (Akt) phosphorylation in the case of A1, A2A, A2B and ERK 1/2 phosphorylation in the case of A3 receptors. Ado, through the activation of A3 and A2B receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1α dependent way. Furthermore ado, through the A2B subtype, induces an increase of Interleukin-8 (IL-8) secretion in a ERK 1/2, p38 and Akt kinases-dependent but not HIF-1α-mediated way. Finally, adenosine stimulates FC formation and this effect is strongly reduced by A3 and A2B blockers and by HIF-1α silencing. In conclusion this study provides the first evidence that A3, A2B or mixed A3/A2B antagonists may be useful to block important steps in the atherosclerotic plaque development adoinduced