Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1 |
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Authors: | Jones Gareth E Prigmore Elena Calvez Ronan Hogan Catherine Dunn Graham A Hirsch Emilio Wymann Matthias P Ridley Anne J |
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Affiliation: | Randall Centre, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK. |
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Abstract: | Phosphoinositide 3-kinases (PI3Ks) are important regulators of cell migration. The PI3K isoform gamma is primarily expressed in haematopoietic cells, and is activated by G protein-coupled receptors (GPCRs). Here, we investigate the contribution of PI3Kgamma to macrophage responses to chemoattractants, using bone marrow-derived macrophages from wild-type and PI3Kgamma-null mice. We observe that early membrane ruffling induced by MCP-1, which activates a GPCR, or by CSF-1, which activates a tyrosine kinase receptor, is unaltered in PI3Kgamma(-/-) mice, although by 30 min MCP-1-induced cell polarization was strongly reduced in PI3Kgamma(-/-) compared to wild-type macrophages. The migration behaviour of the macrophages was analysed by time-lapse microscopy in Dunn chemotaxis chambers. PI3Kgamma(-/-) macrophages showed reduced migration speed and translocation, and no chemotaxis to MCP-1. Interestingly, there was also a reduction in migration efficiency in PI3Kgamma(-/-) macrophages stimulated with CSF-1 although early CSF-1R signalling was normal. These results indicate that the initial actin reorganization induced by either a GPCR or tyrosine kinase receptor agonist is not dependent on PI3Kgamma, whereas PI3Kgamma is needed for optimal migration of macrophages to either agonist. |
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Keywords: | Macrophage G protein-coupled receptor PI 3-kinases Chemokines Tyrosine kinase receptors CSF-1 MCP-1 Actin cytoskeleton Cell migration Chemotaxis |
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