Abstract
Atherosclerotic plaque formation is fueled by the persistence of lipid-laden macrophages in the artery wall. The mechanisms by which these cells become trapped, thereby establishing chronic inflammation, remain unknown. Here we found that netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated the migration of macrophages toward chemokines linked to their egress from plaques. Acting via its receptor, UNC5b, netrin-1 inhibited the migration of macrophages directed by the chemokines CCL2 and CCL19, activation of the actin-remodeling GTPase Rac1 and actin polymerization. Targeted deletion of netrin-1 in macrophages resulted in much less atherosclerosis in mice deficient in the receptor for low-density lipoprotein and promoted the emigration of macrophages from plaques. Thus, netrin-1 promoted atherosclerosis by retaining macrophages in the artery wall. Our results establish a causative role for negative regulators of leukocyte migration in chronic inflammation.
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Acknowledgements
We thank J. Goss and W. Groot for technical support; M. Tessier-Lavigne (Stanford University) for Ntn1+/− mice; and T. Kinane (Massachusetts General Hospital) for anti-UNC5b antiserum. Supported by the American Heart Association (0655840T to K.M. and 09POST2080250 to J.M.v.G.), the US National Institutes of Health (RC1HL100815 to K.J.M. and R01HL084312 to E.A.F.), the Heart and Stroke Foundation of Canada (K.J.R.) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (01558/2007-6 to L.R.F. and J.I.A.-L.).
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J.M.v.G. did migration and atherosclerosis studies; M.C.D. did smooth muscle studies and fetal liver cell transplantation; K.J.R. and L.R.F. did mouse atherosclerosis studies, J.I.A.-L., S.P. and B.R. did microscopy; T.D.R., A.J.R. and J.L.F. did biochemical assays; T.O.M. and K.D.O. did immunohistochemical studies of human atheroma; E.D. and E.A.F. assisted in bead-labeling experiments, L.M.S. and A.L.-H. contributed to experimental design, data analysis and provided discussions; K.J.M. designed, analyzed and interpreted the studies and wrote the manuscript with J.M.v.G.
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van Gils, J., Derby, M., Fernandes, L. et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 13, 136–143 (2012). https://doi.org/10.1038/ni.2205
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DOI: https://doi.org/10.1038/ni.2205
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