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  • phosphocholine Mast cells Mast cells are immune

    2024-07-10

    Mast cells. Mast phosphocholine are immune cells of the myeloid lineage and are ubiquitously present in connective tissues [75]. These cells are involved in the modulation of a number of physiological functions, such as vasodilation, angiogenesis, bacterial, and parasite elimination [75]. Moreover, mast cells regulate the functions of several cells types, including dendritic cells, macrophages, T and B cells, fibroblasts, eosinophils, endothelial cells, and epithelial cells [75]. The activation of A2B and A3 on murine mast cells stimulates their degranulation, thus causing histamine, serotonin, chemokine and protease release [1,76]. The role of adenosine receptors in regulating human mast cells is incompletely understood. Studies performed on human mast cells demonstrated that A2B receptors are primarily involved in promoting mast cell degranulation, while A3 receptors mediate anti-inflammatory effects [77]. In addition, the pharmacological stimulation of A3 receptors potentiated FcεRI-induced degranulation of human lung mast cells but not that of skin mast cells, suggesting an involvement of A3 receptors in the bronchoconstrictive response to adenosine in asthmatic subjects, but not in dermatologic allergy responses [78]. Neutrophils. Neutrophils are the most abundant leukocytes in the circulation, representing a first line of defense in the innate arm of the immune system Neutrophils are characterized by large phenotypic heterogeneity and functional versatility, placing these cells as important modulators of both inflammation and immune responses [79]. Neutrophils are an abundant source of adenosine, which in turn regulates neutrophil activation under both normal conditions and in the presence of inflammation [80,81]. In particular, under adverse conditions, neutrophils release ATP via connexin 43 or pannexin 1 hemichannels, which ATP undergoes rapid conversion to adenosine via the CD39/CD73 axis expressed on the neutrophil surface [82]. In addition, in the presence of inflammation adenosine deaminase is deactivated [83] and the expression of equilibrative nucleoside transporters is reduced [81], thereby promoting an accumulation of adenosine in the biophase of neutrophils. Neutrophils are endowed with all four adenosine receptors [82]. A1 receptors facilitate neutrophil chemotaxis, in part, by up-regulating the neutrophil adhesion receptor Mac-1 and by enhancing the expression of the complement receptors [84]. By contrast, both A2A and A2B receptor engagement was found to mediate the inhibition of neutrophil adhesion to endothelial cells [85]. In particular, Yago et al. [86] showed that incubating neutrophils with the selective A2A receptor agonist, ATL313, β2 integrin-mediated neutrophil rolling and adhesion were markedly inhibited both in TNF-challenged murine cremaster muscle postcapillary venules and in ex vivo flow chamber models. Furthermore, ATL313 counteracted the selectin-triggered activation of Src family kinases (SFKs) and p38 MAPK, the chemokine-triggered activation of Ras-related protein 1, and the β2 integrin-triggered activation of SFKs and Vav cytoskeletal regulatory proteins [86]. In another study, the stimulation of A2A receptors with agonist CGS 21680 reduced the phosphorylation of p38 MAPK, Erk-1/2, PI3 K/Akt, Hck, and Syk, protein kinases in neutrophils [87]. A2A receptors were shown also to blunt IL-8 release, a chemokine that is critically involved in promoting the chemoattraction of leukocytes to the inflammatory site, in the activation of phagocytosis and in neutrophil degranulation [88]. Adenosine can modulate neutrophil bactericidal functions. A dual regulatory effect has been reported for adenosine on phagocytosis. Indeed, the activation of A1 receptors augments this process, while the stimulation of A2A receptors was found to reduce the phagocytic activity of neutrophils [89]. In parallel, adenosine has a differential effect on reactive oxygen species (ROS) generation based on the receptor subtype activated [82]. In particular, the stimulation of A1 receptors induces ROS production from activated neutrophils, whereas the activation of A2A receptors down-regulates ROS generation [88,90]. Agonists for A2B or A3 receptors suppressed stimulus-induced superoxide production in wild type but not in A2B or A3 deficient neutrophils, respectively [91,92]. Of note, besides regulating chemotaxis and ROS generation, A3 receptors mediate the formation of filipodia-like projections [93]. Indeed, the selective A3 receptor agonist 2-Cl-IB-MECA promoted the formation and rapid extension of these structures, thus improving bacterial phagocytosis [93] and chemotaxis [94].