We have reported that TLR4, through regulating G-protein-coupled receptor kinases (GRKs), promotes PMN migration. We demonstrated that MIP-2 induces GRK2 and GRK5 expression in PMNs through phosphoinositide-3-kinase (PI3K)-γ signaling, and LPS-activated signaling through the TLR4 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 after the downregulation of GRK2 and GRK5 expression is a critical determinant of PMN migration (79) (Figure 4) .