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    • Pioneering studies on the immunomodulatory role of adenosine

    2023-01-28

    Pioneering studies on the immunomodulatory role of adenosine date back to the early ‘70 s of last century (Fig. 1), when the critical role of this nucleoside in shaping the development and the activity of several immune cell populations was first established [[18], [19], [20], [21], [22]]. This then lead to the identication of a direct correlation between defective adenosine Spiperone hydrochloride and the onset of adenosine deaminase deficiency, a congenital, severe, combined immunodeficiency (ADA-SCID) [[23], [24], [25], [26]]. Subsequently, seminal studies demonstrated a role for adenosine in human lymphocyte maturation and proliferation [21,27] [[28], [29], [30], [31], [32]] as well as in the regulation of lymphocyte activity [22,33,34]. In this context, consistent data also supported the involvement of the adenosine system in mediating the pharmacological effects of several anti-inflammatory and immunomodulating drugs (i.e. methotrexate, salicylates) that are widely used in the clinical practice to manage chronic inflammatory disorders [8,[35], [36], [37], [38], [39], [40], [41], [42], [43]]. The idea of targeting the adenosine system was then advanced by introducing specific novel pharmacological entities for the management of several immune-mediated disorders [44,45]. At present, some of these drugs are under preclinical evaluation with encouraging results [44], while others have already entered the phase of clinical development for the treatment of rheumatoid arthritis [46] or as novel anticancer immunotherapies [12,47].
    The adenosine machinery: enzymes, transporters and receptors Under physiological conditions, intracellular adenosine derives mainly from S-adenosylhomocysteine via S-adenosylhomocysteine hydrolase (Fig. 2) [48]. Once synthesized, adenosine is extruded into the extracellular space via nucleoside transporters [48]. Nucleoside transporters can be divided into two categories based on their molecular and functional features: 1) the concentrative nucleoside transporters (CNTs) including CNT1, CNT2 and CNT3, which normally mediate the intracellular influx of nucleosides against their concentration gradient but can also transport adenosine to the extracellular space [49]; and 2) the equilibrative nucleoside transporters (ENT1, ENT2, ENT3 and ENT4), which facilitate nucleoside passage across cell membranes in either direction based on their concentration gradients [50]. 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 acid 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].