title: Macrophage fusion leading to foreign body giant cell formation persists under phagocytic stimulation by microspheres in vitro and in vivo in mouse models.
abstract: The formation of surface-damaging foreign body giant cells (FBGC) from the fusion of macrophages is considered a hallmark of the foreign body response. Experimental evidence indicates that when macrophages are unable to internalize foreign bodies via phagocytosis due to their large size, they acquire a fusogenic phenotype. The mechanism behind this transformation is unclear, and questions, such as which phenotype takes precedence for co-stimulated macrophages engaged in the foreign body response and whether or not such phenotypic alteration is graded, remain unanswered. By recapitulating fusion in vitro using cell lines and primary mouse bone marrow-derived macrophages, we investigated whether concurrent exposure of macrophages to phagocytic and fusogenic stimuli would limit fusion. Induction of phagocytosis by addition of 3.0 mum-diameter polystyrene microspheres to cells under fusogenic conditions, at ratios of 1:10, 1:1, and 10:1 did not prevent fusion. To determine the effect of microsphere phagocytosis on fusion in vivo, we first determined the kinetics of monocyte recruitment, surface adhesion, and fusion following intraperitoneal implantation of a foreign body in a mouse model. Concomitant or subsequent injection of microspheres resulted in their significant accumulation at the biomaterial surface at 2 weeks, but FBGC were still detected. Our findings indicate that despite increasing the abundance of a phagocytic stimulus (microspheres), significant FBGC formation occurs.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jay
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Skokos
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zeng
authors.forename: Kristin
authors.initials: K
authors.lastname: Knox
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002459:Cell Fusion; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005549:Foreign-Body Reaction / Q000473:pathology; D015743:Giant Cells, Foreign-Body / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D011137:Polystyrenes / Q000494:pharmacology; D019919:Prosthesis Implantation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D011137:Polystyrenes; D015847:Interleukin-4; D020830:rac1 GTP-Binding Protein