Complement-dependent Clearance of Apoptotic Cells by Human Macrophages

TLDR

Apoptotic cells are rapidly cleared by phagocytes, yet the receptors and ligands mediating this process are not fully defined, and complement activation is thought to be essential for efficient clearance in circulation. Phosphatidylserine exposure on apoptotic cells initiates complement activation, depositing C3bi that engages macrophage CR3 and CR4 receptors. Adding serum boosts apoptotic cell uptake more than threefold by activating classical and alternative complement pathways, which coat cells with C3bi and are efficiently recognized by macrophage CR3 and CR4 receptors.

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.