Abstract

Extracellular adenosine-5′-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X4 and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X4-axis in atherosclerosis. Expression of P2X4 was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X4 in atherosclerosis, P2X4-deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X4-deficient mice developed smaller atherosclerotic lesions compared to P2X4-competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X4-deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X4-deficient mice. Moreover, bone marrow derived macrophages isolated from P2X4-deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1β (IL-1β) and IL-6. Additionally, P2X4-deficient mice shared a lower proportion of pro-inflammatory Ly6Chigh monocytes and a higher proportion of anti-inflammatory Ly6Clow monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X4 expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study’s findings for human atherosclerosis. Collectively, P2X4 deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X4 as a potential therapeutic target in the fight against atherosclerosis.

Highlights

  • Extracellular adenosine-5′-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors

  • This study demonstrated for the first time that P­ 2X4-deficiency reduces atherosclerosis and diminishes vascular inflammation

  • It could be shown that ATP-mediated activation of ­P2X4 induced the release of C-X-C motif chemokine-5 (CXCL-5) in primary monocyte‐derived human ­macrophages[33]

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Summary

Introduction

Extracellular adenosine-5′-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. Activation of ­P2X4 in response to high extracellular ATP levels evokes the release of cytokines like Interleukin 6 (IL-6) and tumor necrosis factor α (TNFα), promoting NLRP3-inflammasome signaling as well as activation of endothelial c­ ells[22,23,24]. Based on this background information, the aim of this study is to investigate the role of ­P2X4 in experimental atherosclerosis and vascular inflammation

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