Platelet-neutrophil interaction aggravates vascular inflammation and promotes the progression of atherosclerosis by activating the TLR4/NF-κB pathway.

Platelet-neutrophil interaction is well known for its role in inflammatory diseases; however, its biological role in atherosclerosis (AS) progression remains unclear. Human peripheral blood neutrophils were obtained to compare toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta and myeloid-related proteins 8/14 (Mrp8/14) levels in 22 AS patients with those in 18 healthy controls using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Meanwhile, mouse marrow neutrophils subjected to different treatment were collected for the ELISA assay, cell apoptosis, and Western blot analysis. Normal diet or high-fat diet ApoE(-/-) mice with or without administration of Mrp8/14 antagonist paquinimod were used for plasma collection to measure total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, TNF-alpha, IL-1 beta, Mrp8/14, TLR4, and nuclear factor (NF)-kappa B p65 levels. The results showed that Mrp8/14 and TLR4-mediated inflammatory pathway was activated in neutrophils of AS patients. In vitro experiments demonstrated that platelet-neutrophil interaction promoted the Mrp8/14 release and inhibited neutrophil apoptosis via P-selectin. Furthermore, platelet-neutrophil interaction upregulated TLR4/myeloid differentiation factor 88/NF-kappa B pathway. Conversely, Mrp8/14/TLR4/NF-kappa B interference alleviated AS progression. In conclusion, Mrp8/14/TLR4/NF-kappa B activated by platelet-neutrophil interaction is an important inflammatory signaling pathway for AS pathogenesis.