title: TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes.
abstract: During innate immune responses, the inflammatory CC chemokine receptors CCR1, CCR2, and CCR5 mediate the recruitment of blood monocytes to infected tissues by promoting cell migration in response to chemokines CCL2-5. Toll-like receptors also play an essential role, allowing pathogen recognition by the recruited monocytes. Here, we demonstrate that Toll-like receptor 2 (TLR2) stimulation by lipoteichoic acid (LTA) from Staphylococcus aureus leads to gradual down-modulation of CCR1, CCR2, and CCR5 from the plasma membrane of human blood-isolated monocytes and inhibits chemotaxis. Interestingly, LTA does not promote rapid desensitization of chemokine-mediated calcium responses. We found that the TLR2 crosstalk with chemokine receptors is not dependent on the Toll/interleukin-1 receptor domain-containing adaptor protein, but instead involves phospholipase C, the small G protein Rac1, and is phorbol ester sensitive. Activation of this pathway by LTA lead to β-arrestin-mediated endocytosis of Ser349-phosphorylated CCR5 into recycling endosomes, as does CCL5 treatment. However, LTA-induced internalization of CCR5 is a slower process associated with phospholipase C-mediated and phorbol ester-sensitive phosphorylation. Overall, our data indicate that TLR2 negatively regulates CCR1, CCR2, and CCR5 on human blood monocytes by activating the machinery used to support chemokine-dependent down-modulation and provide a molecular mechanism for inhibiting monocyte migration after pathogen recognition.
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Fox
authors.forename: Elisa
authors.initials: E
authors.lastname: Letellier
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Oliphant
authors.forename: Nathalie
authors.initials: N
authors.lastname: Signoret
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects; D002465:Cell Movement / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D015536:Down-Regulation / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D010766:Phosphorylation; D020239:Receptor Cross-Talk / Q000276:immunology; D054389:Receptors, CCR1 / Q000097:blood*; D054390:Receptors, CCR2 / Q000097:blood*; D019713:Receptors, CCR5 / Q000097:blood*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000097:blood*
chemical_list: C515300:CCR1 protein, human; C515334:CCR2 protein, human; D008070:Lipopolysaccharides; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; C495342:TLR2 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid