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The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques

Nature Immunology volume 13, pages 136–143 (2012)Cite this article

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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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Figure 1: Abundant expression of netrin-1 and UNC5b by macrophage foam cells in atherosclerotic lesions.
Figure 2: Netrin-1 inhibits the migration of macrophages toward CCL2 and CCL19 via UNC5b.
Figure 3: Netrin-1 secreted by foam cells blocks macrophage migration.
Figure 4: Netrin-1 acts as a chemoattractant for SMCs via neogenin.
Figure 5: Targeted deletion of netrin-1 in cells of the immune response results in a lower atherosclerosis burden.
Figure 6: Targeted deletion of netrin-1 in cells of the immune response results in less-complex plaques and promotes macrophage emigration.

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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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Authors and Affiliations

  1. Leon H. Charney Division of Cardiology, Department of Medicine, Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, New York, USA

    Janine M van Gils, Bhama Ramkhelawon, Tathagat D Ray, Katey J Rayner, Sajesh Parathath, Emilie Distel, Jessica L Feig, Alistair J Rayner, Edward A Fisher & Kathryn J Moore

  2. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Merran C Derby

  3. Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte –, Minas Gerais, Brazil

    Luciana R Fernandes & Jacqueline I Alvarez-Leite

  4. Division of Cardiology, University of Washington, Seattle, Washington, USA

    Thomas O McDonald & Kevin D O'Brien

  5. Department of Pediatrics, Program for Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Lynda M Stuart & Adam Lacy-Hulbert

  6. Department of Cell Biology, New York University School of Medicine, New York, New York, USA

    Edward A Fisher & Kathryn J Moore

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Contributions

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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Correspondence to Kathryn J Moore.

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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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