Involvement of mitogen-activated protein kinases in class B scavenger receptor type I-induced phagocytosis of apoptotic cells.

Class B scavenger receptor type I (SR-BI) is a multiligand membrane protein expressed in a variety of cell types. This receptor is responsible for the incorporation of lipids from high density lipoprotein (HDL) by steroidogenic cells, as well as for the phosphatidylserine (PS)-mediated phagocytosis of apoptotic cells by some phagocytic cell types, such as testicular Sertoli cells. Although SR-BI directly binds to PS present on the surface of apoptotic cells, as to whether SR-BI transmits signals to induce engulfment has not been clear. In the present study, we examined this issue using a monoclonal antibody that neutralizes SR-BI activity and a chemical known to be an inhibitor of the SR-BI-mediated incorporation of HDL lipids. The chemical compound inhibited the incorporation of HDL lipids and PS-containing liposomes by an SR-BI-expressing culture cell line, with no effect on the binding of these targets. Similarly, the phagocytosis of PS-exposing apoptotic cells by primary cultured rat Sertoli cells was inhibited in the presence of either reagent, not at the recognition but at the engulfment step. The addition of apoptotic cells or PS-containing liposomes caused a temporal increment of the phosphorylation of all three mitogen-activated protein kinases, p38, extracellular-signal-regulated kinase (ERK) and c-Jun amino-terminal kinase (JNK), in Sertoli cells. The increase of phosphorylated p38 and ERK, but not of phosphorylated JNK, was cancelled in the presence of the monoclonal antibody. Furthermore, the level of Sertoli cell phagocytosis of PS-exposing apoptotic cells, as well as that of PS-containing liposomes, was reduced only when the actions of p38 and ERK were simultaneously repressed. In conclusion, these results indicate that SR-BI, when it binds to PS, transmits signals to activate the mitogen-activated protein kinase pathway, which leads to the induction of the engulfment of PS-exposing apoptotic cells by phagocytic cells.