Clq acts synergistically with phorbol dibutyrate to activate CR1‐mediated phagocytosis by human mononuclear phagocytes

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Abstract
The adherence of human monocytes and culture-derived macrophages to surfaces coated with complement subcomponent Clq has been previously shown to enhance Fc receptor (FcR)-mediated phagocytosis by these cells. We examined the effects of Clq on C3b/C4b receptor (CR1)-mediated phagocytosis by mononuclear phagocytes. A small percentage of human monocytes cultured in the presence of serum became competent to ingest sheep erythrocytes bearing IgM and C4b (EAC4b). This phagocytic activity was enhanced when these cultured-derived macrophages were adhered to Clq-coated surfaces. However, when cultured in a defined serum-free medium, these cells did not ingest EAC4b, even in the presence of Clq. To investigate this differential responsiveness, we studied the effects of Clq in conjunction with cell-activating agents on CR1 activation. Treatment of serum-free cultured monocytes with phorbol dibutyrate (PDBu), prior to addition of the targets, induced these cells to ingest EAC4b. In addition, when exposed to Clq, both the percentage of these PDBu mononuclear phagocytes ingesting EAC4b and the number of targets ingested increased threefold over the level achieved by macrophages treated with PDBu alone. The chemoattractant N-formyl-methionyl-leucyl-phenylalanine did not activate CR1-mediated phagocytosis and did not substitute for PDBu in causing synergy with Clq. Freshly isolated monocytes adhered to human serum albumin-coated glass slides in the absence or presence of PDBu did not phagocytose EAC4b. Also Clq did not stimulate monocyte CRl-mediated phagocytosis. However, addition of PDBu to cells adherent to the Clq surface triggered phagocytosis of EAC4b. The concentration of PDBu and the time of addition of PDBu relative to addition of the EAC4b targets were found to be important parameters for the achievement of maximal synergy in both the freshly isolated and cultured cell systems. This enhanced phagocytic activity was also seen with cells adhered to the purified collagen-like, pepsin-resistant, fragment of Clq. Since this region was previously shown to interact with Clq surface receptors, it appears that occupancy of this receptor is triggering events contributing to the enhanced cellular function. These experiments suggest that Clq and PDBu promote ingestion via CR1 by different but synergistic mechanisms. These data also demonstrate that the CR1-mediated enhancement of phagocytosis is not specific for FcR-mediated ingestion, but also applies to phagocytosis via CR1.

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