LPS-activated Scavenger Receptor SREC-I can Induce entry of TLR4 into Lipid Microdomains, Mediate Signal Transduction and trigger cytokine release

Scavenger receptor associated with endothelial cells I (SREC-I) has been shown to be expressed in dendritic cells (DC) and activated macrophages and to play an important role in endocytosis of antigenic peptides by these cells. As previous studies indicated that SREC-I required Toll-like receptor 4 (TLR4) function for its immune functions in DC, we have examined potential interactions between these two receptors. Indeed, TLR4 became co-localized with SREC-I on association with lipopolysaccharides (LPS) and the receptors were co-internalized at 37oC. SREC-I binding could then promote TLR4-induced signal transduction through the NFĸB and MAP kinase pathways in response to LPS, leading to enhanced cytokine release. The mechanisms behind the activation of TLR4 downstream signaling by association with SREC-I (in the presence of LPS) appear to involve recruitment of TLR4 into cholesterol-rich lipid microdomains on the plasma membrane with the small GTPase Cdc42 and the non-receptor tyrosine kinase Src. Under co...