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. J. Leukoc. Biol. 85: 617-626; 2009.

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

“…MMP-9 has been associated with modulation of infl ammation by extracellular remodeling and signaling during a foreign body reaction. [ 42 ] Emerging evidence suggests the active participation of MMP-9 in clearance of infl ammatory cells [ 43 ] and this is refl ected here in the decrease in lymphocytes in the nDP scaffolds at week 8 and week 27 compared to the other scaffolds groups.…”

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

“…12 IHC was performed to detect macrophages and FBGC with the Mac-3 antibody (1: 500), and neutrophils with the LY-6G/LY-6C antibody (1: 250). MMP-9 was detected with an anti-MMP-9 antibody (1.5 g/mL).…”

“…8,12 Expanded cells (0.5 ϫ 10 6 per well) were plated on a 24-well non-tissue culture treated polystyrene plate (BD Biosciences, Franklin Lakes, NJ) in media containing 10 ng/mL rm GM-CSF and 10 ng/mL rm IL-4. To examine the role of TNF-␣ in fusion, in separate experiments, cells were incubated with increasing dosages (5, 10, or 50 ng/mL) of rm TNF-␣.…”

“…11 Subsequent fusion experiments demonstrated that MCP-1-null macrophages are compromised in fusion because of inability to undergo cytoskeletal remodeling and induce MMP-9 in response to IL-4. 8,12 The present study investigated the hypothesis that the foreign body response in MCP-1-null mice might be tissue-specific by implanting biomaterials intraperitoneally in wild-type (WT) and MCP-1-null mice and comparing the ensuing foreign body response. Histochemical and immunohistochemical analyses indicated a reduction in macrophage adhesion, FBGC formation, and encapsulation in MCP-1-null mice.…”

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

“…Previous studies have noted a variable increase in RPE cell size as well as multinucleation with age (Ts'o & Friedman, 1967, 1968), but the significance of these observations is unclear. Giant cell formation with multinucleation is a normal feature of some cells such as osteoclasts and syncytiotrophoblasts (Park & Askin, 2013; Oh et al ., 2014) and also occurs during pathological processes such as foreign body giant cell formation in macrophages (Vignery, 2005; MacLauchlan et al ., 2009), and in microglial cells in some forms of neurodegeneration (Lee et al ., 1993; Hornik et al ., 2014). Giant cell formation and multinucleation, at least in osteoclasts, are formed by cell fusion, but other mechanisms may also explain cells with multiple nuclei such as phagocytosis of live cells or failure of cytokinesis in dividing cells (Hornik et al ., 2014).…”