Loss of monocyte chemoattractant protein-1 alters macrophage polarization and reduces NFκB activation in the foreign body response

Acta Biomater. 2015 Jan:11:37-47. doi: 10.1016/j.actbio.2014.09.022. Epub 2014 Sep 19.

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.

Keywords: Foreign body giant cell; Foreign body response; Inflammation; Macrophage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • Cellulose / analogs & derivatives*
  • Cellulose / toxicity
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • Dimethylpolysiloxanes / toxicity*
  • Foreign-Body Reaction / chemically induced
  • Foreign-Body Reaction / genetics
  • Foreign-Body Reaction / metabolism*
  • Foreign-Body Reaction / pathology
  • Gene Expression Regulation / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism*
  • Nitriles / pharmacology
  • Sulfones / pharmacology
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*

Substances

  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Dimethylpolysiloxanes
  • NF-kappa B p50 Subunit
  • Nitriles
  • Rela protein, mouse
  • Sulfones
  • Transcription Factor RelA
  • cellulose ester plastic
  • Nfkb1 protein, mouse
  • baysilon
  • Cellulose