The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages 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. 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.
Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
Janine M
JM
van Gils
Merran C
MC
Derby
Luciana R
LR
Fernandes
Bhama
B
Ramkhelawon
Tathagat D
TD
Ray
Katey J
KJ
Rayner
Sajesh
S
Parathath
Emilie
E
Distel
Jessica L
JL
Feig
Jacqueline I
JI
Alvarez-Leite
Alistair J
AJ
Rayner
Thomas O
TO
McDonald
Kevin D
KD
O'Brien
Lynda M
LM
Stuart
Edward A
EA
Fisher
Adam
A
Lacy-Hulbert
Kathryn J
KJ
Moore
D000199:Actins / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002678:Chimera / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009479:Neuropeptides / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D058105:Polymerization; D011956:Receptors, Cell Surface / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; C515460:CCL19 protein, human; C111835:CCL2 protein, human; C515461:Ccl19 protein, mouse; C491768:Ccl2 protein, mouse; D054415:Chemokine CCL19; D018932:Chemokine CCL2; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D009479:Neuropeptides; C000617353:Ntn1 protein, mouse; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C532445:UNC5B protein, human; D000075388:Netrin-1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein