Dr Tongji Hospital of Tongji University, Tongji University School of Medicine Shanghai, Shanghai, China (People's Republic)
Introduction/Rationale: Plaque erosion (PE) is a distinct pathological cause of acute coronary syndrome (ACS), characterized by neutrophil-mediated endothelial injury. However, the specific contribution of neutrophil heterogeneity, particularly low-density neutrophils (LDNs), to PE pathogenesis remains undefined.
Methods: We performed single-cell RNA sequencing and quantitative proteomics on peripheral blood from patients with optical coherence tomography (OCT)-verified PE-ACS, PR-ACS, and healthy controls. Findings were validated using flow cytometry and functional assays. Mechanistic pathways were investigated in an ApoE−/− mouse model of PE and human aortic endothelial cell (HAEC) co-cultures, utilizing CXCR2 inhibitors (AZD-5069) and NET inhibitors (GSK484).
Results: A distinct, pro-inflammatory LDN subset was significantly expanded in PE-ACS patients, correlating strongly with endothelial microvesicles and thrombus burden. These LDNs exhibited an immature (CD10−), hyperactive phenotype with enhanced chemotaxis and neutrophil extracellular trap (NET) release. We identified that these cells are recruited to erosion sites via the CXCL1/2-CXCR2 axis; pharmacological inhibition of CXCR2 significantly ameliorated PE phenotypes in mice. Mechanistically, PE LDN-derived NETs caused endothelial apoptosis and detachment. Specifically, these NETs impaired Annexin A1 (ANXA1)-mediated plasma membrane repair by physically sequestering ANXA1. An ANXA1 mimetic peptide rescued this impairment and reduced thrombus formation in vivo.
Conclusion: PE LDNs constitute a pathogenic neutrophil subset that drives PE-ACS. They are recruited via the CXCL1/2-CXCR2 axis and promote endothelial denudation and thrombosis by releasing NETs that compromise ANXA1-mediated membrane repair. Targeting the PE LDN-NET-ANXA1 axis represents a potential therapeutic strategy for PE.
