title: Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response.
abstract: Implantation of biomaterials elicits a foreign body response characterized by fusion of macrophages to form foreign body giant cells and fibrotic encapsulation. Studies of the macrophage polarization involved in this response have suggested that alternative (M2) activation is associated with more favorable outcomes. Here we investigated this process in vivo by implanting mixed cellulose ester filters or polydimethylsiloxane disks in the peritoneal cavity of wild-type (WT) and monocyte chemoattractant protein-1 (MCP-1) knockout mice. We analyzed classical (M1) and alternative (M2) gene expression via quantitative polymerase chain reaction, immunohistochemistry and enzyme-linked immunosorbent assay in both non-adherent cells isolated by lavage and implant-adherent cells. Our results show that macrophages undergo unique activation that displays features of both M1 and M2 polarization including induction of tumor necrosis factor α (TNF), which induces the expression and nuclear translocation of p50 and RelA determined by immunofluorescence and Western blot. Both processes were compromised in fusion-deficient MCP-1 KO macrophages in vitro and in vivo. Furthermore, inclusion of BAY 11-7028, an inhibitor of NFκB activation, reduced nuclear translocation of RelA and fusion in WT macrophages. Our studies suggest that peritoneal implants elicit a unique macrophage polarization phenotype leading to induction of TNF and activation of the NFκB pathway.
authors.affiliation: Department of Genetics, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Laura Beth
authors.initials: LB
authors.lastname: Moore
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sawyer
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Antonios
authors.initials: A
authors.lastname: Charokopos
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Skokos
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA. Electronic address: themis.kyriakides@yale.edu.
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002482:Cellulose / Q000031:analogs & derivatives* / Q000633:toxicity; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004129:Dimethylpolysiloxanes / Q000633:toxicity*; D005549:Foreign-Body Reaction / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004129:Dimethylpolysiloxanes; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; C498144:Rela protein, mouse; D013450:Sulfones; D051996:Transcription Factor RelA; C020253:cellulose ester plastic; C073701:Nfkb1 protein, mouse; C013830:baysilon; D002482:Cellulose
keywords: Foreign body giant cell; Foreign body response; Inflammation; Macrophage