Abstract 49: The Neuroimmune Guidance Molecule Semaphorin 3e Is Expressed in Macrophages of Advanced Atherosclerotic Plaques and Induces Macrophage Chemostasis
Objective: The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained in plaques are poorly understood. Recently, we reported the involvement of Netrin-1, a neuronal guidance molecule, in promoting chronic inflammation in atherosclerosis by retaining macrophages in plaque. Semaphorins, another class of neuronal guidance molecules, play a critical role in vascular patterning and development, yet little is known about their role in atherosclerosis. The present study evaluates the expression of Sema3E in the setting of atherosclerosis and its contribution to macrophage accumulation in the atherosclerotic plaque.
Methods and Results: Immunofluorescence staining of aortic root plaques from ApoE-/- mice fed a western diet showed abundant expression of Sema3E, as well as its ligand binding receptor PlexinD1, in macrophage foam cells. In vitro, incubation of bone marrow derived macrophages with physiological drivers of plaque inflammation, OxLDL and hypoxia, induced a 3 and 6 fold up-regulation of Sema3E mRNA levels respectively. In addition, Sema3E was also found to be upregulated 4-fold in inflammatory M1 macrophages compared to their more reparative counterpart, M2 macrophages. To understand how this guidance molecule affects macrophage behavior, we treated macrophages with recombinant (r)Sema3E in the presence/absence of CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques. (r)Sema3E blocked actin polymerization and macrophage migration stimulated by CCL19, suggesting that it may act to immobilize these cells in the plaque. Notably, in two different mouse models of atherosclerosis regression, Sema3E mRNA was highly downregulated in macrophages isolated from regressing plaques compared to progressing plaques. Furthermore, the decrease in Sema3E mRNA and protein in regressing plaques coincided with a reduction in plaque macrophage content and an enrichment in markers of M2 macrophages.
Conclusion: Together, these findings suggest a role for Sema3E in promoting macrophage retention in atherosclerosis and highlight the emerging role for negative regulators of leukocyte migration in promoting chronic inflammation.
- © 2012 by American Heart Association, Inc.