title: Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction.
abstract: 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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Ronny
authors.initials: R
authors.lastname: Milde
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK.
authors.forename: Glenys A
authors.initials: GA
authors.lastname: Tennent
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Loesch
authors.affiliation: Kennedy Rheumatology Institute, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Fernando O
authors.initials: FO
authors.lastname: Martinez
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK. Electronic address: m.pepys@ucl.ac.uk.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany; Institute for Systemic Inflammation Research, Universität zu Lübeck, 23538 Lübeck, Germany. Electronic address: admar.verschoor@uksh.de.
authors.forename: Admar
authors.initials: A
authors.lastname: Verschoor
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Helming
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D015726:Giant Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000187:drug effects*; D051381:Rats; D017452:Receptors, IgG / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000682:Amyloid; D039521:CD11c Antigen; D018821:CD18 Antigens; D003176:Complement C3; D016167:Integrin alphaXbeta2; D017452:Receptors, IgG; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate