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PNAS 102 (41): 14729-14734

Copyright © 2005 by the National Academy of Sciences.

IMMUNOLOGY

Netrin-1 inhibits leukocyte migration in vitro and in vivo

Ngoc P. Ly *, Katsumi Komatsuzaki *, Iain P. Fraser *, Anita A. Tseng {dagger}, Parthak Prodhan *, Kathryn J. Moore {dagger}, and T. Bernard Kinane *, {ddagger}

*Laboratory of Developmental Immunology, Department of Pediatrics, and {dagger}Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRJ 1414, Boston, MA 02114

Communicated by Patricia K. Donahoe, Massachusetts General Hospital, Boston, MA, July 29, 2005

Received for publication February 18, 2005.

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.

Key Words: chemotaxis • inflammation • guidance cue

Author contributions: N.P.L., K.J.M., and T.B.K. designed research; N.P.L., K.K., I.P.F., A.A.T., P.P., and T.B.K. performed research; N.P.L., K.K., K.J.M., and T.B.K. analyzed data; and N.P.L., K.J.M., and T.B.K. wrote the paper.

Conflict of interest statement: Massachusetts General Hospital has filed for a patent on netrin-1's anti-inflammatory actions in Drs. Kinane, Ly, and Komatsuzaki's name. This patent has not been issued. This potential patent has been licensed.

Abbreviations: DCC, deleted in colon cancer; UNC5b, UNC5 homologue B; fMLP, formylmethionylleucylphenylalanine.

{ddagger} To whom correspondence should be addressed. E-mail: tkinane{at}partners.org.

© 2005 by The National Academy of Sciences of the USA

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