Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development

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  Figure 1. Putative role of purinergic signaling in driving macrophages and T cell activation in atheroma development. DAMPs (LDL, oxLDL, extracellular ATP) and PAMPs (viruses, microbes, LPS) trigger the production of cytokines and oxygen species by monocytes (1). This induces release of ATP from the endothelial cells and expression of the leukocyte adhesion molecules (vascular cell adhesion molecule 1, VCAM-1; intercellular adhesion molecule 1, ICAM-1) (2) thus prompting adhesion and extravasation of monocytes and lymphocytes (3). Macrophage derived ROS oxidate LDL to oxLDL (4) and stimulate IL-1β and IL-18 production (5). Extracellular ATP is also converted to ADO by CD39 and CD73, which are expressed by the intima cells (6). ADO exerts a down-modulation of the immune response therefore has a protective effect. On the contrary, ATP acts as a proinflammatory molecule inducing the cleavage of CD62L by ADAM17 and T cell polarization to a Th1 phenotype (7). Upon engulfment of oxLDL, macrophages become foam cells (8). The atheroma “necrotic core” (right part of the figure) forms by accumulation of dying foam cells, lipids, cholesterol crystals and immune cells (9). Pro-inflammatory IFN-γ and…

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  Figure 2. Main molecular components of the purinergic signaling network. Nucleotides (ATP, ADP, UTP, UDP, etc.) and nucleosides (ADO) can be released or transported extracellularly as a consequence of shear stress membrane damage, hypoxia, apoptosis, necrosis and infections. Once liberated, they bind and activate purinergic P2 (P2Y and P2X) or P1 (A1, A2A, A2B, A3) receptors. ADO is generated from the enzymatic conversion of ATP/ADP to AMP by the ectonucleoside triphosphate diphosphohydrolase CD39 and with the hydrolysis of AMP to ADO by the ecto-5′-nucleotidase CD73. ADO activates P1 receptors.