Adenosine and Adenosine Receptors in Rheumatoid Arthritis

Melissa Padovan; Fabrizio Vincenzi; Marcello Govoni; Alessandra Bortoluzzi; Pier Andrea Borea; Katia Varani


Int J Clin Rheumatol. 2013;8(1):13-25. 

In This Article

Role of Adenosine in the Control of Inflammation

Substantial lines of evidence suggest that A2AARs are able to mediate the majority of anti-inflammatory effects of endogenous adenosine.[86,87] In particular, the ability of A2AAR activation to suppress cytokine and chemokine expression by immune cells is probably the dominant mechanism involved. Expression of A2AARs has been found on most inflammatory cells, where it exerts various anti-inflammatory actions.[86] In neutrophils, adenosine, acting at A2AARs, regulates the production of different cytokines including TNF-α, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2α and MIP-3α.[88] Studies using A2A-knockout models have shown that A2AAR activation inhibits IL-2 secretion by naive CD4+ T cells thereby reducing their proliferation, confirming the immunosuppressive effects of A2A AR stimulation.[89,90] It has also been demonstrated that A2AARs play an important role in the promotion of wound healing and angiogenesis.[91] Adenosine has been reported to reduce inflammation in several in vivo models, suggesting a potential value of this purine nucleoside as a therapeutic mediator of inflammatory joint disease able to limit articular cartilage degeneration. In synoviocytes obtained from osteoarthritis patients, the activation of A2AARs inhibited p38 MAPK and NF-κB pathways, as well as the production of TNF-α and IL-8.[92] These results indicate that A2AARs may represent a potential target in therapeutic modulation of joint inflammation. Activation of the A2AARs during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In particular, in a model of ischemia-reperfusion liver injury, A2AAR stimulation with the selective agonist ATL146e was associated with decreased inflammation and profoundly protects mouse liver from injury when administered at the time of reperfusion.[93] Adenosine, acting at A2AARs, plays an important role in the pathogenesis of hepatic fibrosis in response to hepatotoxins. In particular, it has been demonstrated that A2AARs are expressed on human hepatic stellate cell lines and A2AAR occupancy promotes collagen production by these cells. Furthermore, mice lacking A2AARs are protected from developing hepatic fibrosis in two different hepatic fibrosis models.[94] It is well reported that hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with A2AARs triggering off signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as 'reporters', while A2AARs serve as 'sensors' of excessive tissue damage.[95] The hypoxia-adenosinergic tissue-protecting mechanism is triggered by inflammatory damage to blood vessels, interruption in oxygen supply, low oxygen tension (i.e., hypoxia) and by the hypoxia-driven accumulation of extracellular adenosine acting via immunosuppressive, cAMP-elevating A2A receptors.[96] Another area where A2AARs signaling has received attention as a potential therapeutic target is the GI tract. Studies have highlighted the protective effects of A2A receptor activation in various animal models of colitis, and these protective effects can be ascribed to two major mechanisms: decrease of inflammatory-cell infiltration and function in the mucosa, and increased activity of Treg cells.[34,89,97] A2AAR stimulation was found to attenuate gastric mucosal inflammation induced by indomethacin, blocking secondary injury due to stomach inflammation through a reduction of myeloperoxidase and proinflammatory cytokines.[98] Adenosine levels are increased in the lungs of individuals with asthma or COPD, and ARs are known to be expressed on most, if not all, inflammatory and stromal cell types involved in the pathogenesis of these diseases.[99] In addition, pharmacological treatment of allergic rats with an A2AAR agonist resulted in diminished pulmonary inflammation.[100] A recent study in an ADA-deficient model demonstrated that genetic removal of A2AARs leads to enhanced pulmonary inflammation, mucus production and alveolar airway destruction.[55] Furthermore, A2AARs induced on iNKT and NK cells reduced pulmonary inflammation and injury in mice with sickle cell disease, improving baseline pulmonary function and preventing hypoxia-reoxygenation-induced exacerbation of pulmonary injury.[101] These data further confirm the involvement of A2AARs in the anti-inflammatory networks in the lung. A study performed in peripheral lung parenchyma demonstrated that affinity and/or density of adenosine receptors are altered in patients with COPD compared with control smokers with normal lung function. Moreover, there was a significant correlation between the density and affinity of adenosine receptors and the forced expiratory volume/forced vital capacity ratio, an established index of airflow obstruction. In particular A2A, as well as A3ARs, was found to be upregulated in COPD patients.[80] This alteration may represent a compensatory response mechanism and may contribute to the anti-inflammatory effects mediated by the stimulation of these receptors. Given the central role of inflammation in asthma and COPD, substantial preclinical research targeted at understanding the function of A2AARs in models of airway inflammation has been performed. In Phase II trials for COPD the use of an A2AAR agonist named UK432,097 that was identified as an inhaled anti-inflammatory drug without an effect on blood pressure was reported with the aim to highlight the impressive pedigree of A2AARs as a potential anti-inflammatory agent.[102] It is well known that the anti-inflammatory effect of adenosine is also mediated by the activation of A3ARs that are present in immune cells and involved in the physiopathologic regulation of inflammatory and immune processes. Several results from in vitro and in vivo studies suggest that the activation of the A3ARs can be both pro- or anti-inflammatory depending on the cell type examined or on the animal species considered.[103] Binding and functional studies have shown that human neutrophils expressed A3ARs primarily coupled to the inhibition of adenylate cyclase and calcium signaling, mediating the inhibition of oxidative burst, representative of anti-inflammatory activity.[104] A3ARs are also responsible for the inhibition of superoxide production and chemotaxis of mouse bone marrow neutrophils.[105] It has been reported that A3ARs are present on human eosinophils, coupled to signaling pathways linked to cell activation and are able to protect eosinophils from apoptosis and inhibit the chemotaxis process.[76] The effects produced by A3AR activation of macrophages seem to indicate an anti-inflammatory effect of this receptor subtype. In particular, A3ARs suppressed TNF-α release induced by endotoxin CD14 receptor signal transduction pathway from human monocytes and murine macrophages.[38] A3ARs directly control histamine release by antigen-stimulated mouse mast cells, because the stimulatory effect of exogenous adenosine noted in wild-type mast cells is not observed in A3AR-knockout mast cells.[106] Literature data support a role for adenosine in dictating dendritic cell function, promoting the recruitment of immature dendritic cells to sites of inflammation and injury via A3AR.[107,108] It has been proposed that the anti-inflammatory effect elicited by A3AR activation could involve the inhibition of the PI3K/Akt and NF-κB signaling pathways.[109,110] The stimulation of A3ARs decreased proliferation and exerted a cytotoxic and proapoptotic effect on malignant mesothelioma cells and on human healthy mesothelial cells exposed to asbestos through the deregulation of the Akt/NF-κB cell survival pathway.[111] The possibility that A3ARs plays a role in the development of cancer has aroused considerable interest in recent years. In particular, A3ARs were found to be highly expressed in tumor cells and tissues but not in normal cells or adjacent tissue. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors.[79,112]