Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO–ACS study

• Published in: European Heart Journal Vol. 44; no. 38; pp. 3892 - 3907
• Main Authors: Meteva, Denitsa, Vinci, Ramona, Seppelt, Claudio, Abdelwahed, Youssef S, Pedicino, Daniela, Nelles, Gregor, Skurk, Carsten, Haghikia, Arash, Rauch-Kröhnert, Ursula, Gerhardt, Teresa, Straessler, Elisabeth, Zhao, Yingjie, Golla, Felix, Joner, Michael, Rai, Himanshu, Kratzer, Adelheid, Arnal, Hector Giral, Liuzzo, Giovanna, Klotsche, Jens, Crea, Filippo, Landmesser, Ulf, Leistner, David M, Kränkel, Nicolle
• Format: Journal Article
• Language: English
• Published: US Oxford University Press (OUP) 12.10.2023; Oxford University Press
• Subjects: Matrix metalloproteinase 9; Hyaluronic acid; Toll-like receptor 2; Plaque erosion; Neutrophils; Endothelial cell death
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehad379

Abstract Background and aims 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. Methods and results 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. Conclusion 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. Structured Graphical Abstract Structured Graphical Abstract TLR2, Toll-like receptor 2; HA, hyaluronic acid; MMP9, matrix metalloproteinase 9; HYAL2, hyaluronidase 2.