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    • In the presence of detrimental conditions such as

    2022-11-30

    In the presence of detrimental conditions, such as inflammation, hypoxia, ischemia trauma or neoplastic milieu, the extracellular levels of adenosine increase massively, reaching micromolar range [51,52]. In these pathological contexts, adenosine accumulation stems from increased extracellular dephosphorylation of ATP, which is mediated by in a sequential manner by ecto- nucleotide triphosphate diphosphohydrolase-1 (also named CD39) and by ecto-5′-nucleotidase (CD73) (Fig. 2) [9]. A number of studies have identified CD73 as a critical check point in regulating the duration and the magnitude, of the “adenosine halo” surrounding immune cells [47]. In addition to the CD39-CD73 axis, adenosine can be generated through an alternative catabolic pathway (Fig. 2), which is initiated by the nicotinamide adenine dinucleotide (NAD+) glycohydrolases/CD38 enzyme axis that converts extracellular NAD+ into adenosine diphosphate ribose (ADPR)[53]. ADPR is then processed by CD203a into AMP, which is subsequently metabolized by CD73 to adenosine [53]. Once released into the extracellular space, adenosine concentration is fine-tuned by re-uptake into the cells through the nucleoside transporters, as well as through its conversion into inosine by adenosine deaminase both inside and outside the cell [1,45,54], which ultimately leads to the generation of the stable end product uric ProteOrange by xanthine oxidase (Fig. 2) [55]. The biological actions of extracellular adenosine are mediated by G protein-coupled cell-surface receptors, distinguished into four subtypes: A1, A2A, A2B and A3 (Fig. 2) [5]. A1 and A3 receptors are coupled to Gi, Gq and Go proteins [5]. Their stimulation can also elicit the release of calcium ions from intracellular stores [5]. A2A and A2B receptors, which are linked to Gs or Golf, stimulate adenylyl cyclase [5]. A2B receptors can also cause phospholipase C activation through Gq [5]. In addition, all adenosine receptors are coupled to mitogen activated protein kinase (MAPK) pathways, such as extracellular signal-regulated kinase 1 (ERK1), ERK2, p38 MAPK and JUN N terminal kinase [5].
    Adenosine receptors and innate immunity Monocytes and macrophages. All four adenosine receptor subtypes are expressed on monocytes and macrophages, and their levels and function undergo significant changes during the maturation of macrophages from monocytes. Indeed, quiescent monocytes are characterized by a low expression of A1, A2A and A3 receptors, while their density increases during differentiation into macrophages [56]. Receptor expression is regulated by the several pro-inflammatory cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce increases in A2A receptor expression on human monocytes. In addition, these cytokines, through inhibiting A2A receptor desensitization by preventing G-protein coupled receptor kinase 2 (GRK2) and β-arrestin association, enhance receptor function [57]. By contrast, the IFN-γ reduces the expression of A2A receptors [38]. Adenosine itself can regulate receptor expression: adenosine induces heme oxygenase-1 (HO-1) via A2A receptor engagement, and the resultant increased HO-1 enzymatic activity in turn selectively increases the expression of the A2A via the generation of carbon monoxide [58]. In this context, the increase in the A2A receptor expression increases the sensitivity of macrophages toward the anti-inflammatory effect of adenosine [58]. Pro-inflammatory stimuli also regulate macrophage A2B receptors expression [59]. In particular, A2B receptors expression increases following TLR stimulation, leading ProteOrange to the generation of a macrophage phenotype characterized by an increased sensitivity to the immunosuppressive extracellular adenosine [59]. By contrast, IFN-γ inhibited A2B expression, thus mitigating macrophage sensitivity to adenosine and preventing macrophage transition towards an immunoregulatory/immunosuppressive phenotype [59]. Several studies indicate that adenosine, by activating A2A, A2B and A3 receptors, restrains the macrophage production of several pro-inflammatory mediators such as TNF, IL-6, IL-12, nitric oxide (NO) and macrophage inflammatory protein (MIP)-1α [4,36,[60], [61], [62], [63], [64], [65], [66]]. In parallel, extracellular adenosine promotes the release of the anti-inflammatory cytokine IL-10 by monocytes and macrophages via A2A and A2B receptors [10,35,38,67]. A3 receptors can also modulation macrophage migration towards apoptotic cells. In this regard, Joós et al. [68] demonstrated that the autocrine ATP release and its subsequent conversion into adenosine is essential to preserve the velocity and direction of macrophages towards apoptotic thymocytes. In this context, the deletion of A3 gene delayed the kinetics of apoptotic cell clearance, thus highlighting the relevance for this receptor subtype in this context.