Ly et al. discovered that netrin-1, which acts as a guidance cue in neuronal pathfinding, might also play a role in regulating leukocyte migration. Signals that attract leukocytes to inflamed or infected tissue play a critical role in the immune response and have thus been intensively investigated. But what keeps leukocytes--and their potentially destructive effects--out of healthy tissues? Ly et al., a research group who recently showed that the netrin-1 receptor UNC5b is expressed in immune tissues (as well as in lung and brain), combined reverse transcription polymerase chain reaction (RT-PCR) with immunohistochemistry to show that netrin-1 was expressed on vascular endothelial cells. In mice infected with Staphylococcus aureus (to elicit lung inflammation), a decrease in the abundance of lung netrin-1 mRNA coincided with an increase in the abundance of mRNA for the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) (whose increased expression in the lung is known to coincide with leukocyte infiltration). Further, TNF-α and IFN-γ decreased the abundance of netrin-1 mRNA and protein in cultured human umbilical vein endothelial cells (HUVEC). UNC5b was expressed on the surface of monocytes, lymphocytes, and granulocytes, and netrin-1 inhibited monocyte migration to formylmethionylleucylphenylalanine (fMLP, an effect that was blocked by antibodies to UNC5b), granulocyte migration to interleukin-8, and lymphocyte migration to stromal cell-derived factor. Further, intraperitoneal (i.p.) injection of netrin-1 inhibited migration of leukocytes to the peritoneum of mice injected i.p. with fMLP (in a model of peritonitis). Thus, the authors propose that netrin-1 inhibits leukocyte migration into healthy tissue and that its down-regulation by inflammatory cytokines permits leukocyte migration to sites of infection and inflammation.
N. P. Ly, K. Komatsuzaki, I. P. Fraser, A. A. Tseng, P. Prodhan, K. J. Moore, T. B. Kinane, Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 102, 14729-14734 (2005). [Abstract] [Full Text]