title: The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation.
abstract: The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals. In this study, we implanted biomaterials subcutaneous (s.c.) in mice that lack the monocyte chemoattractant CC chemokine ligand 2 (CCL2) and found that biomaterials were encapsulated despite reduced FBGC formation. The latter was due to compromised macrophage fusion rather than migration. Consistent with the reduction in FBGC formation, biodegradable biomaterials sustained reduced damage in CCL2-null mice. Furthermore, blockade of CCL2 function by localized gene delivery in wild-type mice hindered FBGC formation, despite normal monocyte recruitment. The requirement for CCL2 in fusion was confirmed by the ability of both a CCL2 inhibitory peptide and an anti-CCL2 Ab to reduce FBGC formation from peripheral blood monocytes in an in vitro assay. Our findings demonstrate a previously unreported involvement of CCL2 in FBGC formation, and suggest that FBGC are not the primary determinants of capsule formation in the FBR.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington, USA.
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Foster
authors.forename: Grant E
authors.initials: GE
authors.lastname: Keeney
authors.forename: Annabel
authors.initials: A
authors.lastname: Tsai
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
authors.forename: Ian
authors.initials: I
authors.lastname: Clark-Lewis
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001672:Biocompatible Materials / Q000008:administration & dosage; D002459:Cell Fusion; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019742:Chemokines, CC / Q000378:metabolism; D005260:Female; D015743:Giant Cells, Foreign-Body / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001672:Biocompatible Materials; D018932:Chemokine CCL2; D019742:Chemokines, CC; D008024:Ligands; D010446:Peptide Fragments