Leukocyte-Specific CCL3 Deficiency Inhibits Atherosclerotic Lesion Development by Affecting Neutrophil Accumulation

Abstract

Objective-Despite common disbelief that neutrophils are involved in atherosclerosis, evidence is accumulating for a causal role of neutrophils in atherosclerosis. CC chemokine ligand (CCL)3 is an inflammatory chemokine and its expression is significantly increased during atherosclerotic lesion formation in mice. It has recently been shown that under conditions of inflammation neutrophils can migrate along a CCL3 gradient. In this study, we aimed to elucidate the role of leukocytederived CCL3 in atherogenesis. Methods and Results-Irradiated low density lipoprotein receptor -/-mice, reconstituted with CCL3 -/-or littermate bone marrow showed markedly reduced CCL3 response to lipopolysaccharide treatment, establishing the critical relevance of leukocytes as source of CCL3. Hematopoietic deficiency of CCL3 significantly reduced aortic sinus lesion formation by 31% after 12 weeks of western-type diet. Interestingly, whereas plaque macrophage, collagen, and vascular smooth muscle cell content were unchanged, neutrophil adhesion to and presence in plaques was significantly attenuated in CCL3 -/-chimeras. These mice had reduced circulating neutrophil numbers, which could be ascribed to an increased neutrophil turnover and CCL3 -/-neutrophils were shown to be less responsive toward the neutrophil chemoattractant CXC chemokine ligand 1. Conclusion-Our

Chemokines in Atherosclerosis

“…Although CCL3 deficiency in Ldlr −/− mice had no effects on atherosclerotic lesion formation in the aortic sinus, chimeric Ldlr −/− mice reconstituted with Ccl3 −/− bone marrow displayed a decrease in plaque burden in the aortic root. 13,14 These protective effects were associated with lower lipid levels in blood and decreased adipose tissue mass but no changes in circulating leukocyte populations in 1 study. 13 Conversely, de Jager et al 14 ascribed decreased plaque formation to a reduction in lesional neutrophil accumulation as a consequence of decreased neutrophil adhesion and recruitment into plaques.…”

“…13,14 These protective effects were associated with lower lipid levels in blood and decreased adipose tissue mass but no changes in circulating leukocyte populations in 1 study. 13 Conversely, de Jager et al 14 ascribed decreased plaque formation to a reduction in lesional neutrophil accumulation as a consequence of decreased neutrophil adhesion and recruitment into plaques. In addition, CCL3 was revealed to extend the half-life of neutrophils and to interfere with their apoptosis but not maturation or stromal release from bone marrow, leading to diminished circulating neutrophil counts in mice with CCL3-deficient bone marrow.…”

“…Findings that only hematopoietic but not global deficiency of CCL3 affects lesion formation remain to be elucidated, but suggest that CCL3 specifically secreted from leukocytes (and in particular macrophages and neutrophils 14 ) or site-specific effects of its production exert proatherogenic functions in atherosclerosis (Table).…”

Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression

“…Subsequently neutrophils were isolated by magnetic bead isolation (magneticactivated cell sorting LS column, Miltenyi). We obtained neutrophils at z90% purity, as validated by flow cytometry and histology [25], which were used for further experiments.…”

Chemokines

“…However, de Jager et al 18 were the first to provide evidence for a causal relationship between leukocyte-derived CCL3 and atherogenesis. Hematopoietic deficiency of CCL3 reduced atherosclerotic lesion size, without changing plaque macrophage, collagen, and SMC content.…”