Abstract
Rationale Monocytes play a major role in atherosclerosis progression through migration into the arterial wall. Neutrophil involvement in atherosclerosis was previously only thought to be via enzymatic weakening of the fibrous cap. However, neutrophil depletion can delay atherogenesis and conversely increasing circulating neutrophil enhance plaque progression in mice. Lack of evidence for the presence of neutrophils in atherosclerotic plaques makes their role in disease progression less clear. We have found neutrophil-derived microparticles increase migration of neutrophils. Our hypothesis: neutrophil-derived microparticles increase endothelial cell-monocyte interactions and facilitate monocyte transendothelial migration. Methodology Neutrophils were incubated with various agents to stimulate microparticle formation. Microparticles were characterised and quantified using a novel, standardised flow cytometry method and electron microscopy. Monocytes were migrated to MCP-1 across CAEC incubated with neutrophil-derived microparticles using a transendothelial migration assay. Cytokine release and adhesion molecule expression by hCAEC was investigated using a cytometric bead array and fluorescent antibody binding respectively. Microparticle adhesion to hCAECs was investigated under static and flow conditions. Findings Neutrophil-derived microparticles were between 0.5 and 0.9µm. The most abundant surface markers were Annexin V with 20-30% positive microparticles, CD66c (10–15%) and CD18 (5–15%). Low levels of CD11b, CXCR2, and L-selectin were observed. More microparticles were produced in response to fMLP and aLDL compared to PBS. Microparticles bind to and induce MCP-1 release from hCAEC. Monocyte migration increased upon hCAEC incubation with neutrophil-derived microparticles and the extent of the increase was dependent on the stimulus used with aLDL>fMLP>PBS. This highlights a role for microparticles in endothelial activation.
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