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

doi:10.1016/j.celrep.2015.10.065

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

^*Corresponding author for this work

Institute of Systemic Inflamation Research

129 Citations (Scopus)

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.

Original language	English
Journal	Cell Reports
Volume	13
Issue number	9
Pages (from-to)	1937-1948
Number of pages	12
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2015.10.065
Publication status	Published - 01.12.2015

Funding

We thank Dirk Busch, Patrick Rämer (both Technische Universität München), and Falk Nimmerjahn (Universität Erlangen-Nuernberg) for helpful comments on the manuscript, reagents, and/or experimental advice and Vanessa Landtwing (University of Zurich) for assistance with 3D visualizations. Christie Ballantyne (Baylor College of Medicine) kindly shared Itgax- knockout mice. We thank Karl Bodin, Melvyn Kahan, and Janet Gilbertson (University College London) for in vivo experiments in anti-SAP-treated mice and routine histology. This work was funded by the German Research Foundation (DFG) with grants HE 5190/3-1 to L.H. and SFB 914 (B4) to A.V. and the UK Medical Research Council Programme and Project grants to M.B.P. and G.A.T. We gratefully acknowledge support by the Technische Universität München Graduate School and the Wolfson Foundation at University College London.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2015.10.065

Cite this

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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.",

author = "Ronny Milde and Julia Ritter and Tennent, \{Glenys A.\} and Andrzej Loesch and Martinez, \{Fernando O.\} and Siamon Gordon and Pepys, \{Mark B.\} and Admar Verschoor and Laura Helming",

note = "Funding Information: We thank Dirk Busch, Patrick R{\"a}mer (both Technische Universit{\"a}t M{\"u}nchen), and Falk Nimmerjahn (Universit{\"a}t Erlangen-Nuernberg) for helpful comments on the manuscript, reagents, and/or experimental advice and Vanessa Landtwing (University of Zurich) for assistance with 3D visualizations. Christie Ballantyne (Baylor College of Medicine) kindly shared Itgax- knockout mice. We thank Karl Bodin, Melvyn Kahan, and Janet Gilbertson (University College London) for in vivo experiments in anti-SAP-treated mice and routine histology. This work was funded by the German Research Foundation (DFG) with grants HE 5190/3-1 to L.H. and SFB 914 (B4) to A.V. and the UK Medical Research Council Programme and Project grants to M.B.P. and G.A.T. We gratefully acknowledge support by the Technische Universit{\"a}t M{\"u}nchen Graduate School and the Wolfson Foundation at University College London. Publisher Copyright: {\textcopyright} 2015 The Authors. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

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AU - Milde, Ronny

AU - Ritter, Julia

AU - Tennent, Glenys A.

AU - Loesch, Andrzej

AU - Martinez, Fernando O.

AU - Gordon, Siamon

AU - Pepys, Mark B.

AU - Verschoor, Admar

AU - Helming, Laura

N1 - Funding Information: We thank Dirk Busch, Patrick Rämer (both Technische Universität München), and Falk Nimmerjahn (Universität Erlangen-Nuernberg) for helpful comments on the manuscript, reagents, and/or experimental advice and Vanessa Landtwing (University of Zurich) for assistance with 3D visualizations. Christie Ballantyne (Baylor College of Medicine) kindly shared Itgax- knockout mice. We thank Karl Bodin, Melvyn Kahan, and Janet Gilbertson (University College London) for in vivo experiments in anti-SAP-treated mice and routine histology. This work was funded by the German Research Foundation (DFG) with grants HE 5190/3-1 to L.H. and SFB 914 (B4) to A.V. and the UK Medical Research Council Programme and Project grants to M.B.P. and G.A.T. We gratefully acknowledge support by the Technische Universität München Graduate School and the Wolfson Foundation at University College London. Publisher Copyright: © 2015 The Authors. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2015/12/1

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N2 - 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.

AB - 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.

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ER -

Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction

Abstract

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Research Areas and Centers

UN SDGs

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