Neuroimmune Guidance Cue Semaphorin 3E Is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention

Abstract

Objective The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained are poorly understood. Semaphorins, a class of neuronal guidance molecules, play a critical role in vascular patterning and development, and recent studies suggest that they may also have immunomodulatory functions. The present study evaluates the expression of Semaphorin 3E (Sema3E) in settings relevant to atherosclerosis and its contribution to macrophage accumulation in plaques. Approach and Results Immunofluorescence staining of Sema3E, and its receptor PlexinD1, demonstrated their expression in macrophages of advanced atherosclerotic lesions of Apoe–/– mice. Notably, in two different mouse models of atherosclerosis regression, Sema3E mRNA was highly downregulated in plaque macrophages, coincident with a reduction in plaque macrophage content and an enrichment in markers of reparative M2 macrophages. In vitro, Sema3E mRNA was highly expressed in inflammatory “M1” macrophages, and in macrophages treated with physiological drivers of plaque progression and inflammation, such as oxidized LDL and hypoxia. To explore mechanistically how Sema3E affects macrophage behavior, we treated macrophages with recombinant protein in the presence/absence of chemokines, including CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques. Sema3E blocked actin polymerization and macrophage migration stimulated by the chemokines, suggesting that it may immobilize these cells in the plaque. Conclusions Sema3E is up-regulated in macrophages of advanced plaques, is dynamically regulated by multiple atherosclerosis-relevant factors, and acts as a negative regulator of macrophage migration, which may promote macrophage retention and chronic inflammation in vivo.

Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s)

“…15 Recently, it was shown that coronary endothelial cells normally express NTN1, which potently inhibits migration of monocytes in vitro. 26 Our results of downregulation of NTN1 in advanced plaques are supported by the finding that proatherogenic factors (oscillatory shear stress, proinflammatory cytokines) downregulate NTN1 expression in vitro.…”

The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

“…Thus, Slit2 could represent an exciting therapeutic candidate to simultaneously inhibit the individual events that collectively promote the initiation and progression of vascular inflammation associated with atherosclerosis. Other guidance cues, such as ephrin B2, netrin1, and semaphorin 3E, are differentially regulated in proatherogenic conditions; however, overall, these factors appear to exacerbate, and not attenuate, progressive vascular injury (47)(48)(49). Further studies are needed to determine whether Slit2 is unique among these cues, preventing early trafficking of monocytes into affected vessels, as we report in this article, as well as advanced lesion progression.…”

Genetics of Coronary Artery Disease

“…The axon guidance pathways modulate diverse biological phenomena, including cellular adhesion, migration, proliferation, differentiation, survival, and synaptic plasticity, through the participation of highly conserved families of guidance molecules, including netrins, slits, semaphorins, and ephrins, and their cognate receptors 117 and members of these pathways have been highlighted in many recent reports related to macrophage migration, 118 expression of inflammatory markers and M2 signals in atherosclerotic plaque, 119 and chemokine-directed migration of human monocytes. 120,121 Network centrality analysis further identified genes (eg, NCAM1, FYN, and FURIN) likely to play critical roles in the maintenance and functioning of several of the replicated pathways.…”