br Acknowledgement This work was supported by grants from th

Acknowledgement This work was supported by grants from the American Heart Association Scientist Development Grant (SDG) to A. Elmarakby and 1R01EY023315-01 award to M. Al-Shabrawey.
Introduction Inflammatory response is the result of a complex interaction between immune ulixertinib and several soluble factors, aimed at protecting the host from invasion by microorganisms and eliminate debris at sites of tissue injury in order to maintain tissue homeostasis [1,2]. However, an exuberant immune/inflammatory response, not adequately balanced by endogenous mechanisms of homeostatic control, can lead to persistent and abnormal forms of collateral tissue damage [1,2]. In this regard, adenosine, a purine nucleoside that accumulates in the extracellular space at sites of tissue damaged is a pivotal player in the modulation of immune responses and in restraining inflammatory tissue damage [1]. Indeed, over the years, a number of studies have identified extracellular adenosine as a ‘retaliatory metabolite’, which indicates that it is generated as a result of cellular injury or stress, and that through interacting with specific G protein-coupled receptors, it regulates the immune/inflammatory cell functions[[3], [4], [5]] to protect tissues from injury and stress [[5], [6], [7], [8], [9], [10], [11]]. However, chronic exposure to adenosine may under some conditions may be harmful, as adenosine can create an immunosuppressed niche, which is necessary for the onset and development of neoplasia and infection [[12], [13], [14], [15], [16]] [17]. 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 metabolism 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].