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  • br Adenosine receptors and innate immunity Monocytes and

    2024-06-07


    Adenosine receptors and innate ONX-0912 australia 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 ONX-0912 australia 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 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. In the past few years, several experimental findings have demonstrated a pivotal involvement of adenosine also in driving the phenotypic switch of macrophages. In particular, the stimulation of A2A and A2B receptors seems to play a critical role in switching macrophages from M1 to M2 phenotype [37,69]. Dendritic cells. Dendritic cells (DCs) are professional antigen-presenting cells, whose main role is to activate adaptive immunity, thereby maintaining immune homeostasis and tolerance [70]. Adenosine has been shown to regulate several dendritic cell functions [1]. Immature human DCs express mainly A1 and A3 receptors, which are involved in the regulation of chemotaxis via an increase in intracellular calcium. Mature DCs mainly express A2A receptors, which reduce the release of pro-inflammatory cytokines [71]. A2B receptors have pro-inflammatory effects on dendritic cells as they can switch the differentiation of bone marrow cells to a CD11c+,Gr-1+ dendritic cell subset that promotes a Th17 response [72]. In addition, adenosine deaminase and A2B receptor form a molecular complex on dendritic cells that by interacting with CD26 expressed on T cells elicits TNF and IFN-γ production by these cells [73]. Novitskiy et al. [74] showed that A2B receptors drive DC differentiation towards a pro-angiogenic, pro-inflammatory phenotype. Indeed, the activation of A2B receptors, by endogenous adenosine generated in a hypoxic milieu, stimulates the release of IL-6, IL-8, IL-10, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), indoleamine 2,3 dioxygenase and cyclooxygenase (COX)-2, all of which have pro-angiogenic effects [74].