Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1.
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.
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D021961:Cell Membrane Structures / Q000378:metabolism; D002464:Cell Migration Inhibition; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D019204:GTP-Binding Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D018932:Chemokine CCL2; D007527:Isoenzymes; D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins