Recognition of pathogens by the Toll-like receptors (TLRs) activates the innate immune response to help the host eliminate the pathogen. Bacteria have developed various mechanisms to thwart this system. Hajishengallis et al. report that the Porphyromonas gingivalis fimbriae (Pg-fimbriae), which are hairlike appendages on the surface of the bacteria, not only can activate TLR2 signaling but also can bind and activate the chemokine receptor CXCR4 and promote an interaction between CXCR4 and TLR2 that inhibits TLR2 signaling. Fluorescence resonance energy transfer (FRET) experiments performed on cells in which lipid rafts were intact or pharmacologically disrupted revealed that Pg-fimbriae promoted an interaction between CXCR4 and TLR2 in lipid raft regions of the plasma membrane. When the cells were treated with an antibody that blocked CXCR4, Pg-fimbriae promoted a stronger activation of the transcription factor NF-κB and decreased production of the immunosuppressive cytokine IL-10, which suggested that the TLR2 response to Pg-fimbriae was inhibited when CXCR4 was functional. Experiments with Chinese hamster ovary (CHO) cells that were transfected with CXCR4 demonstrated that Pg-fimbriae bound directly to CXCR4. Comparison of cells transfected with TLR2 and its co-receptor CD14 with or without transfection of CXCR4 showed that although Pg-fimbriae activated NF-κB signaling in the cells expressing CD14 and TLR2, this response was decreased in cells also expressing CXCR4. Pg-fimbriae promoted the CXCR4-mediated accumulation of cAMP and subsequent activation of protein kinase A, and pharmacological inhibition of either of these prevented Pg-fimbriae from inhibiting TLR2-mediated signaling. When mouse phagocytes were exposed to P. gingivalis and CXCR4 activity or cAMP synthesis or PKA activity was blocked, there was enhanced production of nitric oxide, which is involved in TLR2-mediated killing of the bacteria. Mice in which CXCR4 activity was inhibited cleared the bacteria more effectively than did control mice. Thus, the fimbriae of P. gingivalis appear to evade the host immune system by inhibiting TLR responses through activation of an inhibitory signal initiated in response to binding to CXCR4.
G. Hajishengallis, M. Wang, S. Liang, M. Triantafilou, K. Triantafilou, Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function. Proc. Natl. Acad. Sci. U.S.A. 105, 13532-13537 (2008). [Abstract] [Full Text]