Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT

Blood. 2011 Nov 17;118(20):5622-30. doi: 10.1182/blood-2011-03-344242. Epub 2011 Sep 22.

Abstract

Localization of plasmin on macrophages and activation of pro-MMP-9 play key roles in macrophage recruitment in the inflammatory response. These functions are promoted by plasminogen receptors exposing C-terminal basic residues on the macrophage surface. Recently, we identified a novel transmembrane plasminogen receptor, Plg-R(KT), which exposes a C-terminal lysine on the cell surface. In the present study, we investigated the role of Plg-R(KT) in macrophage invasion, chemotactic migration, and recruitment. Plg-R(KT) was prominently expressed in membranes of human peripheral blood monocytes and monocytoid cells. Plasminogen activation by urokinase-type plasminogen activator (uPA) was markedly inhibited (by 39%) by treatment with anti-Plg-R(KT) mAb. Treatment of monocytes with anti-Plg-R(KT) mAb substantially inhibited invasion through the representative matrix, Matrigel, in response to MCP-1 (by 54% compared with isotype control). Furthermore, chemotactic migration was also inhibited by treatment with anti-Plg-R(KT) mAb (by 64%). In a mouse model of thioglycollate-induced peritonitis, anti-Plg-R(KT) mAb markedly inhibited macrophage recruitment (by 58%), concomitant with a reduction in pro-MMP-9 activation in the inflamed peritoneum. Treatment with anti-Plg-R(KT) mAb did not further reduce the low level of macrophage recruitment in plasminogen-null mice. We conclude that Plg-R(KT) plays a key role in the plasminogen-dependent regulation of macrophage invasion, chemotactic migration, and recruitment in the inflammatory response.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Biocompatible Materials
  • Cell Movement / drug effects
  • Cell Movement / immunology*
  • Collagen
  • Disease Models, Animal
  • Drug Combinations
  • Female
  • Fibrinolysin / metabolism
  • Fibrinolysin / pharmacology
  • Humans
  • Laminin
  • Macrophages / cytology*
  • Macrophages / immunology
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Monocytes / cytology
  • Monocytes / immunology
  • Peritonitis / chemically induced
  • Peritonitis / immunology*
  • Peritonitis / metabolism
  • Plasminogen / genetics
  • Plasminogen / immunology*
  • Plasminogen / metabolism
  • Proteoglycans
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism
  • Receptors, Urokinase Plasminogen Activator / immunology
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Thioglycolates / toxicity

Substances

  • Antibodies, Monoclonal
  • Biocompatible Materials
  • Drug Combinations
  • Laminin
  • PLG-R(KT) protein, mouse
  • PLGRKT protein, human
  • Proteoglycans
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Thioglycolates
  • matrigel
  • Plasminogen
  • Collagen
  • Fibrinolysin
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse