Trapped in the Plaque

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Science Signaling  31 Jan 2012:
Vol. 5, Issue 209, pp. ec35
DOI: 10.1126/scisignal.2002901

Atherosclerotic plaques are characterized by cholesterol-filled macrophages (“foam cells”) that contribute to expansion of the lesion and establishment of a chronic inflammatory milieu. Noting that resolution of acute inflammation involves emigration of monocyte-derived cells and that netrin-1—which provides both repulsive and attractive guidance cues to axons—inhibits leukocyte migration, van Gils et al. explored its role in macrophage retention in atherosclerotic plaques. Immunohistochemical staining of human atherosclerotic plaques identified netrin-1 and its receptor UNC5b in macrophages. Similarly, immunofluorescence analysis revealed colocalization of netrin-1 with macrophages and extracellular netrin-1 in macrophage-rich regions of plaques in mouse models of atherosclerosis [mice lacking the LDL (low-density lipoprotein) receptor (Ldlr–/– mice) or mice lacking apolipoprotein E (ApoE–/– mice)]. Cholesterol loading (induced by diet in Ldlr–/– or ApoE–/– mice or by treating isolated macrophages with oxidized LDL) increased the abundance of mRNAs encoding netrin and UNC5b in isolated mouse peritoneal macrophages, with increased netrin-1 confirmed by immunoblot analysis of lysates and by ELISA of conditioned medium. Netrin-1 inhibited migration of peritoneal macrophages and of a macrophage cell line toward the chemokines CCL2, CCL19, and CCL21 and inhibited chemokine-dependent activation of Rac1, phosphorylation of the adhesion kinase FAK, and actin polymerization. Conditioned medium from macrophages treated with oxidized LDL also inhibited migration toward chemokine, an effect attenuated with medium from macrophages lacking netrin-1 (Ntn1–/– macrophages). In contrast to its effect on macrophages, netrin-1 acted as a chemoattractant for human coronary artery smooth muscle cells, as did conditioned medium from macrophages treated with oxidized LDL. Ldlr–/– mice reconstituted with Ntn1–/– hematopoietic cells after bone marrow ablation showed decreased diet-induced atherosclerosis compared to those reconstituted with wild-type hematopoietic cells, with atherosclerotic plaques containing fewer macrophages and fewer smooth muscle cells. Moreover, in vivo analyses of macrophages labeled with fluorescent beads were consistent with increased emigration from plaques of Ntn1–/– macrophages compared with wild-type macrophages. The authors thus conclude that, by limiting the emigration of macrophages and enhancing the recruitment of smooth muscle cells, netrin-1 promotes the progression of atherosclerotic lesions.

J. M. van Gils, M. C. Derby, L. R. Fernandes, B. Ramkhelawon, T. D. Ray, K. J. Rayner, S. Parathath, E. Distel, J. L. Feig, J. I. Alvarez-Leite, A. J. Rayner, T. O. McDonald, K. D. O’Brien, L. M. Stuart, E. A. Fisher, A. Lacy-Hulbert, K. J. Moore, The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat. Immunol. 13, 136–143 (2012). [PubMed]

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