P2X(7) Deficiency Blocks Lesional Inflammasome Activity and Ameliorates Atherosclerosis in Mice

Article

关键词: P2X7 RECEPTOR;    INTERLEUKIN-1-BETA INHIBITION;    VASCULAR INFLAMMATION;    ATP;    ACTIVATION;    DISEASE;    CANAKINUMAB;    THROMBOSIS;    RELEASE;    MACROPHAGES;   

DOI  :  10.1161/CIRCULATIONAHA.117.027400

来源: SCIE

【 摘 要 】

BACKGROUND: Extracellular adenosine triphosphate (ATP) binds as a danger signal to purinergic receptor P2X(7) and promotes inflammasome assembly and interleukin-1 beta expression. We hypothesized a functional role of the signal axis ATP-P2X(7) in inflammasome activation and the chronic inflammation driving atherosclerosis. METHODS: P2X(7)-competent and P2X(7)-deficient macrophages were isolated and stimulated with lipopolysaccharide, ATP, or both. To assess whether P2X(7) may have a role in atherosclerosis, P2X(7) expression was analyzed in aortic arches from low density lipoprotein receptor-/-mice consuming a high-cholesterol or chow diet. P2X(7) +/+ and P2X(7)(-/-) low density lipoprotein receptor(-/-) mice were fed a high-cholesterol diet to investigate the functional role of P2X(7) knockout in atherosclerosis. Human plaques were derived from carotid endarterectomy and stained against P2X(7). RESULTS: Lipopolysaccharide or ATP stimulation alone did not activate caspase 1 in isolated macrophages. However, priming with lipopolysaccharide, followed by stimulation with ATP, led to an activation of caspase 1 and interleukin-1 beta in P2X(7)-competent macrophages. In contrast, P2X(7)-deficient macrophages showed no activation of caspase 1 after sequential stimulation while still expressing a basal amount of interleukin1 beta. P2X(7) receptor was higher expressed in murine atherosclerotic lesions, particularly by lesional macrophages. After 16 weeks of a high-cholesterol diet, P2X(7)-deficient mice showed smaller atherosclerotic lesions than P2X(7) competent mice (0.162 cm(2) +/- 0.023 [n=9], P2X(7)(-/-) low density lipoprotein receptor(-/-) : 0.084 cm(2) +/- 0.01 [n=11], P=0.004) with a reduced amount of lesional macrophages. In accord with our in vitro findings, lesional caspase 1 activity was abolished in P2X(7)(-/-) mice. In addition, intravital microscopy revealed reduced leukocyte rolling and adhesion in P2X(7)-deficient mice. Last, we observe increased P2X(7) expression in human atherosclerotic lesions, suggesting that our findings in mice are relevant for human disease. CONCLUSIONS: P2X(7) deficiency resolved plaque inflammation by inhibition of lesional inflammasome activation and reduced experimental atherosclerosis. Therefore, P2X(7) represents an interesting potential new target to combat atherosclerosis.

【 授权许可】

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