The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques.
Nat Immunol
; 13(2): 136-43, 2012 Jan 08.
Article
in En
| MEDLINE
| ID: mdl-22231519
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Movement
/
Tumor Suppressor Proteins
/
Atherosclerosis
/
Plaque, Atherosclerotic
/
Macrophages
/
Nerve Growth Factors
Type of study:
Guideline
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2012
Type:
Article
Affiliation country:
United States