Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors

Nat Med. 2003 Mar;9(3):315-21. doi: 10.1038/nm832. Epub 2003 Feb 18.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Movement / physiology*
  • Chemokine CXCL2
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Down-Regulation / physiology
  • Drosophila Proteins*
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • G-Protein-Coupled Receptor Kinase 5
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Monokines / metabolism
  • Neutrophils / drug effects
  • Neutrophils / physiology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Chemokine / metabolism*
  • Signal Transduction / physiology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • beta-Adrenergic Receptor Kinases

Substances

  • Chemokine CXCL2
  • Drosophila Proteins
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Monokines
  • Receptors, Cell Surface
  • Receptors, Chemokine
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • Grk5 protein, mouse
  • Mitogen-Activated Protein Kinases