Abstract
Migration is a basic feature of many cell types in a wide range of species. Since the 1800s, cell migration has been proposed to occur in the nervous and immune systems, and distinct molecular cues for mammalian neurons and leukocytes have been identified. Here we report that Slit, a secreted protein previously known for its role of repulsion in axon guidance and neuronal migration, can also inhibit leukocyte chemotaxis induced by chemotactic factors. Slit inhibition of the chemokine-induced chemotaxis can be reconstituted by the co-expression of a chemokine receptor containing seven transmembrane domains and Roundabout (Robo), a Slit receptor containing a single transmembrane domain. Thus, there is a functional interaction between single and seven transmembrane receptors. Our results reveal the activity of a neuronal guidance cue in regulating leukocyte migration and indicate that there may be a general conservation of guidance mechanisms underlying metazoan cell migration. In addition, we have uncovered an inhibitor of leukocyte chemotaxis, and propose a new therapeutic approach to treat diseases involving leukocyte migration and chemotactic factors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Chemokine CXCL12
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Chemokines, CXC / metabolism
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Chemokines, CXC / pharmacology
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Chemotactic Factors / pharmacology
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Chemotactic Factors / physiology*
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Chemotaxis, Leukocyte* / drug effects
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Gene Expression
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Glycoproteins*
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HL-60 Cells
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Humans
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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N-Formylmethionine Leucyl-Phenylalanine / pharmacology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / pharmacology
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Nerve Tissue Proteins / physiology*
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Neutrophils / drug effects
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Neutrophils / metabolism
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Neutrophils / physiology
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Rats
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Receptors, CXCR4 / physiology
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Receptors, Immunologic / physiology
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Respiratory Burst / drug effects
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Roundabout Proteins
Substances
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Chemotactic Factors
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Glycoproteins
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Nerve Tissue Proteins
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Receptors, CXCR4
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Receptors, Immunologic
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slit protein, vertebrate
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N-Formylmethionine Leucyl-Phenylalanine
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases