The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting macrophage emigration from plaques

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. Netrin-1, a neuroimmune guidance cue, was secreted by macrophages in human and mouse atheroma, where it inactivated macrophage migration to chemokines implicated in their egress from plaques. Acting via its receptor UNC5b, netrin-1 inhibited CCL2- and CCL19-directed macrophage migration, Rac1 activation and actin polymerization. Targeted deletion of netrin-1 in macrophagesseverely diminished atherosclerosis progression in Ldlr(−/−) mice and promoted macrophage emigration from plaques. Thus, netrin-1 promotes atherosclerosis by retaining macrophages in the artery wall and establish a causative role for negative regulators of leukocyte migration in chronic inflammation.