Methods and Results: 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. Besides, P2X₄-deficient mice shared a lower proportion of pro-inflammatory Ly6C^high monocytes and a higher proportion of anti-inflammatory Ly6C^low monocytes. 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.

Conclusion: Altogether P2X₄ deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming. Therefore, P2X₄ represents an interesting potential therapeutic target in the fight against atherosclerosis.