Abstract | BACKGROUND: METHODS: 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-1β in P2X7-competent macrophages. In contrast, P2X7-deficient macrophages showed no activation of caspase 1 after sequential stimulation while still expressing a basal amount of interleukin-1β. P2X7 receptor was higher expressed in murine atherosclerotic lesions, particularly by lesional macrophages. After 16 weeks of a high- cholesterol diet, P2X7-deficient mice showed smaller atherosclerotic lesions than P2X7-competent mice (0.162 cm2±0.023 [n=9], P2X7-/- low density lipoprotein receptor-/- : 0.084 cm2±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 P2X7-/- mice. In addition, intravital microscopy revealed reduced leukocyte rolling and adhesion in P2X7-deficient mice. Last, we observe increased P2X7 expression in human atherosclerotic lesions, suggesting that our findings in mice are relevant for human disease. CONCLUSIONS:
|
Authors | Peter Stachon, Adrian Heidenreich, Julian Merz, Ingo Hilgendorf, Dennis Wolf, Florian Willecke, Sunaina von Garlen, Philipp Albrecht, Carmen Härdtner, Nicolas Ehrat, Natalie Hoppe, Jochen Reinöhl, Constantin von Zur Mühlen, Christoph Bode, Marco Idzko, Andreas Zirlik |
Journal | Circulation
(Circulation)
Vol. 135
Issue 25
Pg. 2524-2533
(Jun 20 2017)
ISSN: 1524-4539 [Electronic] United States |
PMID | 28377486
(Publication Type: Journal Article)
|
Copyright | © 2017 American Heart Association, Inc. |
Chemical References |
- Inflammasomes
- Lipopolysaccharides
- Receptors, Purinergic P2X7
- Adenosine Triphosphate
|
Topics |
- Adenosine Triphosphate
(toxicity)
- Animals
- Atherosclerosis
(chemically induced, metabolism, prevention & control)
- Humans
- Inflammasomes
(antagonists & inhibitors, metabolism)
- Inflammation
(chemically induced, metabolism, prevention & control)
- Lipopolysaccharides
(toxicity)
- Macrophages
(drug effects, metabolism)
- Male
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Purinergic P2X7
(deficiency)
|