Complement-dependent Clearance of Apoptotic Cells by Human Macrophages

Abstract

Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.

Platelet Mediated Complement Activation

“…Since PS is present on early apoptotic cells (Vermes, Haanen, Steffen-Nakken, and Reutelingsperger 1995), we propose that complement activation on microparticles may be involved in physiologic clearance mechanisms. Indeed, complement components C1q, Factor B, and C3 have all been shown to participate in the phagocytosis of apoptotic cells (Mevorach, Mascarenhas, Gershoev, and Eldon 1998).…”

Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

“…The binding of C1q, which is found in low levels in some patients with SLE, to apoptotic cells was first described by Ahearn and colleagues (14,15), and the importance of complement in the scavenging process is becoming more and more evident. Several studies have suggested an association between the classical complement pathway and the clearance of early apoptotic and secondary necrotic cells (14,(16)(17)(18).…”

“…The role of complement and other adaptor molecules in the opsonization and clearance of apoptotic cells has been established (14,16,18,20,21). During apoptosis, chromatin is degraded by internal proteases and nucleases before the cells lose their membrane integrity.…”

Disposal of dying cells: A balancing act between infection and autoimmunity

“…Usually, apoptotic cells are cleared in the early phase of cell death. However, recent studies showed that some backup mechanisms may exist that enable the safe removal of late apoptotic cells that have escaped regular, early scavenging (47,64,65). When the recognition system of the phagocytes fails, "danger" may be overcome, "safety" may be illusory, and autoimmunity and infection result.…”

“…Many recent reports favor the hypothesis that deficient clearance of apoptotic cells by phagocytes may lead to the accumulation of late apoptotic as well as secondary necrotic cells, which induce the proinflammatory microenvironment that challenges the T cell tolerance (20,33,34,(44)(45)(46)(47)(48)(49)(50)(51)(52). When cells undergoing apoptosis are not properly cleared, they may enter late stages of apoptosis and secondary necrosis consecutively.…”