Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors.
Polymorphonuclear leukocytes (PMNs) are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites and killing pathogenic microbes. We addressed the role of chemokine receptor desensitization induced by G-protein-coupled receptor kinases (GRKs) in the feedback control of PMN migration. We show that the chemokine macrophage inflammatory protein-2 (MIP-2) induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-gamma signaling. We also show that lipopolysaccharide (LPS)-activated signaling through the Toll-like receptor (TLR)-4 pathway transcriptionally downregulates the expression of GRK2 and GRK5 in response to MIP-2. The reduced expression of GRKs lowers chemokine receptor desensitization and markedly augments the PMN migratory response. These data indicate that TLR4 modulation of PMN surface chemokine receptor expression subsequent to the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration.
Fan
Jie
J
Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Malik
Asrar B
AB
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D054426:Chemokine CXCL2; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D029721:Drosophila Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D015846:Monokines / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051552:beta-Adrenergic Receptor Kinases
D054426:Chemokine CXCL2; D017868:Cyclic AMP-Dependent Protein Kinases; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D054774:G-Protein-Coupled Receptor Kinase 5; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D015846:Monokines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051552:beta-Adrenergic Receptor Kinases; C495345:TLR4 protein, human; C517898:GRK5 protein, human; C517895:Grk5 protein, mouse