title: Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9.
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.
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: MacLauchlan
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Skokos
authors.forename: Norman
authors.initials: N
authors.lastname: Meznarich
authors.forename: Dana H
authors.initials: DH
authors.lastname: Zhu
authors.forename: Sana
authors.initials: S
authors.lastname: Raoof
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002459:Cell Fusion; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000473:pathology; D005547:Foreign Bodies; D015726:Giant Cells / Q000473:pathology; D015743:Giant Cells, Foreign-Body / Q000473:pathology*; D015847:Interleukin-4 / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D015847:Interleukin-4; D020780:Matrix Metalloproteinase 9