Figure 4

Model of TLR4 and chemokine receptor cross-talk. MIP-2 binding to CXCR2 induces PMN migration, as well as GRK2 and GRK5 expression, through PI3K-γ signaling. Increased GRK2 and GRK5 expression results in chemokine receptor internalization and desensitization, thereby negatively regulating PMN migration. Thus, PI3K-γ-activated signaling is postulated to be a feedback mechanism regulating PMN migration. Because persistent infection requires continued PMN infiltration, LPS acting through the TLR4 signaling pathway transcriptionally downregulates expression of GRK2 and GRK5 in response to MIP-2. This decreases chemokine receptor desensitization by preventing CXCR2 internalization and thus augments PMN migration. MEK kinase is involved in mediating the cross-talk between TLR4 and chemokine receptors. Dashed lines indicate inhibitory signals. (The figure is adapted from (79); and for it, J Fan acknowledges first publication in Nature Medicine.)