Abstract
The phagocytosis of apoptotic cells is a complex process involving numerous interactions between the target cell and the macrophage. We have examined a role of the major soluble inhibitor of the classic and lectin complement pathways, C4b-binding protein (C4BP), in the clearance of apoptotic cells. The major form of C4BP present in blood is composed of seven alpha-chains and one beta-chain, which binds protein S (PS). Approximately 70% of all PS in human plasma is trapped in such a complex and is able to localize C4BP to the surface of apoptotic cells due to the high affinity to phosphatidylserine. Free PS has recently been shown to enhance phagocytosis of apoptotic cells by macrophages. We observed a stimulatory effect of free PS on the engulfment of apoptotic cells (BL-41 and Jurkat) by primary human macrophages or THP-1 cells and a decrease of activity in serum depleted of PS in agreement with previous results. However, we also show that the process is strongly inhibited in the presence of the C4BP-PS complex. Addition of the C4BP-PS complex to serum deficient in both molecules abolished the enhancing effect of serum on phagocytosis. The effect of both free PS and the C4BP-PS complex could be inhibited with monoclonal antibody directed against the Gla domain of PS. Although the presence of the C4BP-PS complex on apoptotic cells may lead to decreased phagocytosis, it may still be beneficial to the host, since it could prevent secondary necrosis because it inhibits further complement attack.
Highlights
The process of apoptosis marks superfluous cells with signals that direct recognition, engulfment, and degradation by phagocytes in a very complex process involving a number of molecules present on the apoptotic cell and the macrophage as well as molecules recruited from serum
The presence of the C4b-binding protein (C4BP)-protein S (PS) complex on apoptotic cells may lead to decreased phagocytosis, it may still be beneficial to the host, since it could prevent secondary necrosis because it inhibits further complement attack
The sex hormone binding globulin (SHBG)-like region consists of two laminin G-like domains (LG domains) both of which are involved in a high affinity binding to the -chain of an abundant complement inhibitor C4b-binding protein (C4BP) [8]
Summary
The process of apoptosis marks superfluous cells with signals that direct recognition, engulfment, and degradation by phagocytes in a very complex process involving a number of molecules present on the apoptotic cell and the macrophage as well as molecules recruited from serum. We observed a stimulatory effect of free PS on the engulfment of apoptotic cells (BL-41 and Jurkat) by primary human macrophages or THP-1 cells and a decrease of activity in serum depleted of PS in agreement with previous results. The effect of both free PS and the C4BP-PS complex could be inhibited with monoclonal antibody directed against the Gla domain of PS.
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