Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction
Ronny Milde,
Julia Ritter,
Glenys A. Tennent,
Andrzej Loesch,
Fernando O. Martinez,
Siamon Gordon,
Mark B. Pepys,
Admar Verschoor,
Laura Helming
Affiliations
Ronny Milde
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
Julia Ritter
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
Glenys A. Tennent
Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK
Andrzej Loesch
Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK
Fernando O. Martinez
Kennedy Rheumatology Institute, University of Oxford, Oxford OX3 7LD, UK
Siamon Gordon
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Mark B. Pepys
Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK
Admar Verschoor
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
Laura Helming
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
Multinucleated giant cells (MGCs) form by fusion of macrophages and are presumed to contribute to the removal of debris from tissues. In a systematic in vitro analysis, we show that IL-4-induced MGCs phagocytosed large and complement-opsonized materials more effectively than their unfused M2 macrophage precursors. MGC expression of complement receptor 4 (CR4) was increased, but it functioned primarily as an adhesion integrin. In contrast, although expression of CR3 was not increased, it became functionally activated during fusion and was located on the extensive membrane ruffles created by excess plasma membrane arising from macrophage fusion. The combination of increased membrane area and activated CR3 specifically equips MGCs to engulf large complement-coated targets. Moreover, we demonstrate these features in vivo in the recently described complement-dependent therapeutic elimination of systemic amyloid deposits by MGCs. MGCs are evidently more than the sum of their macrophage parts.
