IMMUNOBIOLOGY TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes

During innate immune responses, the in-flammatory CC chemokine receptors CCR1, CCR2, and CCR5 mediate the re-cruitment of blood monocytes to infected tissues by promoting cell migration in response to chemokines CCL2-5. Toll-like receptors also play an essential role, al-lowing pathogen recognition by the re-cruited monocytes. Here, we demon-strate 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 hu-man blood-isolated monocytes and inhib-its chemotaxis. Interestingly, LTA does not promote rapid desensitization of che-mokine-mediated calcium responses. We found that the TLR2 crosstalk with chemo-kine receptors is not dependent on the Toll/interleukin-1 receptor domain-con-taining adaptor protein, but instead in-volves phospholipase C, the small G pro-tein Rac1, and is phorbol ester sensitive. Activation of this pathway by LTA lead to -arrestin–mediated endocytosis of Ser349-phosphorylated CCR5 into recy-cling endosomes, as does CCL5 treat-ment. However, LTA-induced internaliza-tion of CCR5 is a slower process associated with phospholipase C–medi-ated and phorbol ester–sensitive phos-phorylation. 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 patho-gen recognition. (Blood. 2011;117(6): 1851-1860