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

van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, Rayner AJ, McDonald TO, O'Brien KD, Stuart LM, Fisher EA, Moore KJ, Adam Lacy-Hulbert

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)136-43
Number of pages8
JournalNature Immunology
Volume13
Issue number2
DOIs
Publication statusPublished - 8 Jan 2012

Keywords / Materials (for Non-textual outputs)

  • ATHEROSCLEROSIS
  • Cell Movement
  • Chemokine CCL2
  • Chemokine CCL19
  • Nerve Growth Factor
  • Plaque, Atherosclerotic
  • POLYMERIZATION
  • Tumor Suppressor Protein
  • rac GTP-Binding Proteins

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