BACKGROUND: Atherosclerotic plaque destabilization is promoted by inflammatory cell recruitment, tissue cell death, and mechanical weakening. Neutrophils drive vascular tissue injury and perpetuate inflammation and represent a viable therapeutic opportunity. Here, we identify a distinct subset of activated neutrophils within atherosclerotic lesions that express the chemokine receptor CCR2 (C-C chemokine receptor type 2), which directs their migration toward areas enriched with smooth muscle cells and contributes to plaque instability. METHODS: mice. RESULTS: neutrophils preferentially populate mouse and human atherosclerotic lesions and display a proinflammatory phenotype with enhanced capacity for reactive oxygen species production and neutrophil extracellular trap release. Genetic or pharmacological CCR2 inhibition reduced neutrophil migration and infiltration to the atherosclerotic lesion, reducing their presence in smooth muscle cell-rich areas. Consistently, neutralization of the CCR2 ligand CCL2 decreased lesional neutrophil numbers and preserved fibrous cap integrity by increasing smooth muscle cell content and decreasing features associated with plaque instability. CONCLUSIONS: Our data suggest that a subset of CCR2-expressing neutrophils senses smooth muscle cell-derived CCR2 ligands to infiltrate and promote vulnerable atherosclerotic lesions. These results support that neutrophil functional heterogeneity within the atherosclerotic lesions alters lesion stability. Specific targeting thereof may improve plaque stability without impacting host defense.
Farjia et al. (Thu,) studied this question.