Abstract 17630: Leukocyte Specific CCL3 Deficiency Inhibits Atherosclerotic Lesion Development by Attenuation of Intimal Neutrophil Accumulation
Introduction: Migration of leukocytes into the vessel wall is an essential step in atherosclerotic lesion formation and progression, and chemokines are regarded as key regulators of this process. Macrophage Inflammatory Protein 1 alpha (MIP1α or CCL3), a member of the CC chemokine family can bind and signal via chemokine receptors such as CCR1, and CCR5, which were previously shown to be implicated in atherogenesis. In this study we aimed to elucidate the role of leukocyte derived CCL3 in atherogenesis.
Methods and Results: Irradiated LDLr−/− mice, reconstituted with CCL3−/− or littermate bone marrow showed markedly reduced CCL3 response to LPS treatment (P<0.001), establishing the critical relevance of leukocytes as source of CCL3. Lesion formation in the aortic sinus in CCL3−/− chimeras after 12 weeks of western type diet feeding was significantly impaired (−31%, P<0.05). While collagen, macrophage and T cell content of plaques of CCL3−/− chimeras were essentially similar to that of littermate controls, neutrophil adhesion to and presence in plaques was significantly attenuated (−60%, P=0.001). Under non inflammatory conditions circulating neutrophil numbers did not differ between WT and CCL3−/− mice, whereas they were markedly decreased in CCL3−/− mice upon LPS treatment. Kinetic analysis of neutrophils after cyclosphosphamide treatment showed accelerated depletion in CCL3−/− mice pointing to a reduced neutrophil half life. CCL3−/− neutrophils were less responsive towards the neutrophil chemo-attractant KC
Conclusions: Taken together our data indicate that under conditions of acute inflammation leukocyte derived CCL3 can induce neutrophil chemotaxis towards the atherosclerotic plaque, thereby accelerating lesion formation.
- © 2010 by American Heart Association, Inc.