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Originally published online as doi:10.1189/jlb.1008588 on January 13, 2009

Published online before print January 13, 2009
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(Journal of Leukocyte Biology. 2009;85:617-626.)
© 2009 by Society for Leukocyte Biology

Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9

Susan MacLauchlan*,1, Eleni A. Skokos*,1, Norman Meznarich{dagger}, Dana H. Zhu*, Sana Raoof*, J. Michael Shipley{ddagger}, Robert M. Senior{ddagger}, Paul Bornstein{dagger} and Themis R. Kyriakides*,2

* Interdepartmental Program in Vascular Biology and Therapeutics and Departments of Pathology and Biomedical Engineering, Yale University, New Haven, Connecticut, USA;
{dagger} Departments of Biochemistry and Medicine, University of Washington, Seattle, Washington, USA; and
{ddagger} Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

2 Correspondence: Yale University, Department of Pathology, 10 Amistad St., 301 C, New Haven, CT 06520, USA. E-mail: themis.kyriakides{at}yale.edu

ABSTRACT

Macrophages undergo fusion to form multinucleated giant cells in several pathologic conditions, including the foreign body response (FBR). We detected high levels of matrix metalloproteinase (MMP)-9 during macrophage fusion in vitro and in foreign body giant cells (FBGCs) in vivo. Wild-type (WT) bone marrow-derived macrophages were induced to fuse with IL-4 in the presence of MMP-9 function-blocking antibodies and displayed reduced fusion. A similar defect, characterized by delayed shape change and abnormal morphology, was observed in MMP-9 null macrophages. Analysis of the FBR in MMP-9 null mice was then pursued to evaluate the significance of these findings. Specifically, mixed cellulose ester disks and polyvinyl alcohol sponges were implanted s.c. in MMP-9 null and WT mice and excised 2–4 weeks later. Histochemical and immunohistochemical analyses indicated equal macrophage recruitment between MMP-9 null and WT mice, but FBGC formation was compromised in the former. In addition, MMP-9 null mice displayed abnormalities in extracellular matrix assembly and angiogenesis. Consistent with a requirement for MMP-9 in fusion, we also observed reduced MMP-9 levels in MCP-1 null macrophages, previously shown to be defective in FBGC formation. Collectively, our studies show abnormalities in MMP-9 null mice during the FBR and suggest a role for MMP-9 in macrophage fusion.

Key Words: monocyte/macrophages • cell fusion • extracellular matrix • angiogenesis