title: Netrin-1 inhibits leukocyte migration in vitro and in vivo.
abstract: Cell migration plays important roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. A number of barriers exist to prevent the inappropriate migration of leukocytes into healthy peripheral tissues, including retention of these cells in the inactive state and maintenance of the integrity and charge of the vascular endothelium. However, active signals also are likely to exist that can repulse cells or abolish existing cell migration. One such paradigm exists in the developing nervous system, where neuronal migration is mediated by a balance between chemoattractive and chemorepulsive signals. The ability of the guidance molecule netrin-1 to repulse or abolish attraction of neuronal cells expressing the UNC5b receptor makes it an attractive candidate for the regulation of inflammatory cell migration. Here, we show that netrin-1 is expressed on vascular endothelium, where it is regulated by infection and inflammatory cytokines. The netrin-1 receptor UNC5b is strongly expressed by leukocytes, upon which netrin-1 acts as a potent inhibitor of migration to different chemotactic stimuli both in vivo and in vitro. These data suggest that endothelial expression of netrin-1 may inhibit basal cell migration into tissues and that its down-regulation with the onset of sepsis/inflammation may facilitate leukocyte recruitment.
authors.affiliation: Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRJ 1414, Boston, MA 02114, USA.
authors.forename: Ngoc P
authors.initials: NP
authors.lastname: Ly
authors.forename: Katsumi
authors.initials: K
authors.lastname: Komatsuzaki
authors.forename: Iain P
authors.initials: IP
authors.lastname: Fraser
authors.forename: Anita A
authors.initials: AA
authors.lastname: Tseng
authors.forename: Parthak
authors.initials: P
authors.lastname: Prodhan
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: T Bernard
authors.initials: TB
authors.lastname: Kinane
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000276:immunology; D017931:DNA Primers; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000276:immunology* / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D017931:DNA Primers; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D013481:Superoxides; D000075388:Netrin-1