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

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.

The Contribution of Vascular Proteoglycans to Atherothrombosis: Clinical Implications

“…Collectively, these findings indicate an important role for platelets in plaque erosion, where hyaluronan is present at the plaque-thrombus interface and few leukocytes infiltrate the vascular wall [9,10,31]. Recent evidence has also demonstrated that increased HYAL-2 in thrombi found on eroded lesions occurs concomitantly with increased local levels of TLR2 ligand hyaluronic acid [131]. Neutrophil expression of TLR2 from patients with eroded plaques was also shown to be elevated compared to patients with ruptured plaques, with enhanced MMP-9 release from neutrophils and endothelial cytotoxicity [131].…”

“…Recent evidence has also demonstrated that increased HYAL-2 in thrombi found on eroded lesions occurs concomitantly with increased local levels of TLR2 ligand hyaluronic acid [131]. Neutrophil expression of TLR2 from patients with eroded plaques was also shown to be elevated compared to patients with ruptured plaques, with enhanced MMP-9 release from neutrophils and endothelial cytotoxicity [131]. Data from this study provides the first in-human evidence that hyalaronic acid may promote endothelial dissociation in plaque erosion through the TLR2 neutrophil axis.…”

Characterization of Biomarkers of Thrombo-Inflammation in Patients with First-Diagnosed Atrial Fibrillation

“…Anticoagulation focuses on the prevention of thromboembolic events [1]. However, activated platelets facilitate acute arterial thrombotic events (e.g., AMI) and release pro-fibrotic and pro-inflammatory mediators [24][25][26]. Therefore, we studied the biomarkers of primary hemostasis during FDAF.…”

Coronary Plaque Erosion: Epidemiology, Diagnosis, and Treatment

“…A recently proposed prevailing theory regarding PE suggests that it involves multiple hits, including distinct activation of neutrophils dependent on toll-like receptor-2 (TLR2) [ 43 ]. This activation is believed to be sustained by an increased local expression of hyaluronidase 2, leading to heightened cleavage of hyaluronic acid at the coronary culprit eroded lesion [ 43 ].…”

“…A recently proposed prevailing theory regarding PE suggests that it involves multiple hits, including distinct activation of neutrophils dependent on toll-like receptor-2 (TLR2) [ 43 ]. This activation is believed to be sustained by an increased local expression of hyaluronidase 2, leading to heightened cleavage of hyaluronic acid at the coronary culprit eroded lesion [ 43 ]. Consequently, this results in the intensified release of active MMP9 by neutrophils, exacerbating the detachment of luminal endothelial cells under disturbed flow conditions [ 43 ].…”