Why Don't Macrophages Leave Atherosclerotic Lesions?

Abstract

### The Neuroimmune Guidance Cue Netrin-1 Promotes Atherosclerosis by Inhibiting the Emigration of Macrophages From Plaques Van Gils et al Nature Immunology . 2012;13:136–143. A recent study proposes a novel role for inhibitory guidance cues in regulating macrophage trafficking during atherosclerosis.1 The study authors demonstrate that Netrin-1, a laminin-related protein with a previously established role in axon migration and tumorigenesis, contributes to atherosclerosis by preventing the emigration of macrophages from plaque. Monocyte recruitment to areas of subendothelial lipid deposition has long been identified as a critical early step in the inflammatory pathophysiology of atherosclerosis.2,3 Less is known, however, about the signals that mediate both the retention and efflux of macrophages from atherosclerotic lesions. Evidence from prior studies has suggested that lipid accumulation promotes the retention of macrophages in atherosclerotic lesions by disrupting CCR7-dependent chemotaxis, which under normal conditions enhances macrophage efflux from sites of inflammation.4–6 Other studies have shown that inhibitory guidance cues mediated by the laminin-related protein Netrin-1 regulate leukocyte migration into infected or ischemic tissues.7–9 Netrin has an established role in neural development and axonal migration according to the expression of activating (eg, neogenin) or inhibitory (eg, UNC5b) receptors on target cells.7,10,11 van Gils et al hypothesized that Netrin may also be involved in blocking egress of macrophages from atherosclerotic plaques, thereby contributing to the chronic inflammatory events that promote lesion growth and destabilization. The authors found expression of Netrin-1 and the inhibitory receptor UNC5b in lesional macrophages in histological sections of human coronary arteries and also showed upregulation of Netrin-1 and UNC5b mRNA in the aortas of Ldlr −/− and Apoe −/− mice fed a high-fat diet. Peritoneal macrophage “foam cells” isolated from these mice also expressed higher levels of Netrin-1 and UNC5b, as did macrophages that had been loaded with ox-LDL (but not LDL) in …