医学
TLR2型
中性粒细胞胞外陷阱
免疫学
病理
MMP9公司
炎症
TLR4型
下调和上调
生物
生物化学
基因
作者
Denitsa Meteva,Ramona Vinci,Claudio Seppelt,Youssef S Abdelwahed,Daniela Pedicino,Gregor Nelles,Carsten Skurk,Aiden Haghikia,Ursula Rauch,Teresa Gerhardt,Elisabeth Tamara Straessler,Yupei Zhao,F. L. Golla,Michael Joner,Himanshu Rai,Adelheid Kratzer,H Giral Arnal,Giovanna Liuzzo,Jens Klotsche,Filippo Crea,Ulf Landmesser,David M Leistner,Nicolle Kraenkel
标识
DOI:10.1093/eurheartj/ehad379
摘要
In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets.Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid.The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS.
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