Immunology Slit: Leukocytes Don't Like it Either

Slit proteins were identified as secreted ligands that mediate neuronal repulsion through interaction with members of the Robo family of single transmembrane receptors. Wu et al. show that Slit2 and Slit3 and the Robo1 receptor are expressed in several nonneuronal tissues. In leukocyte migration assays, Slit2 inhibited migration stimulated by the chemokine SDF-1α and by the bacterial peptide N-formyl-Met-Leu-Phe (fMLP). This result was not simple repulsion, but represented an inhibition of the attraction signaling mechanism, because Slit2 was able to inhibit migration when applied to either the chamber containing the cells or the target chamber. Inhibition of SDF-1α-stimulated migration by Slit2 was reconstituted in human embryonic kidney cells (HEK) by cotransfection of the chemokine receptor CXCR4, a G protein-coupled receptor (GPCR) and Robo1, suggesting an interaction between these two receptors. These data raise several important points: (i) there is crosstalk between GPCRs and the Robo single transmembrane receptor, (ii) there is conservation of molecular mechanisms of guidance pathways across multiple systems (iii) Slit2 and Robo1 represent new avenues of exploration and potential therapeutic targets for controlling leukocyte-mediated inflammatory processes.

J. Y. Wu, L. Feng, H.-T. Park, N. Havlioglu, L. Weng, H. Tang, K. B. Bacon, Z.-h. Jiang, X.-c. Zhang, Y. Rao, The neuronal repellent repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410, 984-952 (2001). [Online Journal]