title: 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.
  
  
  RESULTS
  Immunofluorescence staining of Sema3E, and its receptor PlexinD1, demonstrated their expression in macrophages of advanced atherosclerotic lesions of Apoe(-/-) mice. Notably, in 2 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 low-density lipoprotein 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 upregulated 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.
authors: Marc and Ruti Bell Vascular Biology and Disease Program, Department of Medicine, Leon H. Charney Division of Cardiology, New YorkUniversity School of Medicine, New York, NY 10016, USA.
authors: Amarylis
authors: A
authors: Wanschel
authors: Tara
authors: T
authors: Seibert
authors: Bernd
authors: B
authors: Hewing
authors: Bhama
authors: B
authors: Ramkhelawon
authors: Tathagat D
authors: TD
authors: Ray
authors: Janine M
authors: JM
authors: van Gils
authors: Katey J
authors: KJ
authors: Rayner
authors: Jonathan E
authors: JE
authors: Feig
authors: Edward R
authors: ER
authors: O'Brien
authors: Edward A
authors: EA
authors: Fisher
authors: Kathryn J
authors: KJ
authors: Moore
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D006023:Glycoproteins / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D039961:Semaphorins; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D008565:Membrane Proteins; C111150:Sema3e protein, mouse; D039961:Semaphorins; D020764:cdc42 GTP-Binding Protein