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Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT
Shahrzad Lighvani1, Nagyung Baik, Jenna E Diggs
1Department of Cell Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd., La Jolla, CA 92037, USA.
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.
Insights
A novel plasminogen receptor, Plg-R(KT), on macrophages is crucial for inflammatory cell recruitment. Blocking Plg-R(KT) inhibits macrophage invasion, migration, and recruitment, highlighting its role in inflammation.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Plasminogen receptors on macrophages are vital for inflammatory responses.
- These receptors facilitate plasmin localization and pro-matrix metalloproteinase-9 (pro-MMP-9) activation.
- A novel transmembrane plasminogen receptor, Plg-R(KT), exposing a C-terminal lysine, was recently identified.
Purpose of the Study:
- To investigate the role of the novel plasminogen receptor Plg-R(KT) in macrophage invasion, chemotactic migration, and recruitment.
- To determine the impact of Plg-R(KT) on plasminogen activation and pro-MMP-9 activation in inflammatory processes.
Main Methods:
- Monocytes and monocytoid cells were analyzed for Plg-R(KT) expression.
- The effect of anti-Plg-R(KT) monoclonal antibody (mAb) on plasminogen activation by urokinase-type plasminogen activator (uPA) was assessed.
- Macrophage invasion through Matrigel and chemotactic migration in response to MCP-1 were evaluated.
- Macrophage recruitment in a mouse model of thioglycollate-induced peritonitis was studied.
- Pro-MMP-9 activation in vivo was measured.
- Experiments were conducted in plasminogen-null mice.
Main Results:
- Plg-R(KT) is highly expressed on human peripheral blood monocytes and monocytoid cells.
- Anti-Plg-R(KT) mAb significantly inhibited plasminogen activation by uPA (39%).
- Treatment with anti-Plg-R(KT) mAb substantially inhibited monocyte invasion (54%) and chemotactic migration (64%).
- In vivo, anti-Plg-R(KT) mAb markedly inhibited macrophage recruitment (58%) and reduced pro-MMP-9 activation.
- No further reduction in macrophage recruitment was observed in plasminogen-null mice.
Conclusions:
- Plg-R(KT) plays a critical role in regulating macrophage invasion, chemotactic migration, and recruitment.
- The receptor is essential for plasminogen-dependent processes in the inflammatory response.
- Plg-R(KT) represents a potential therapeutic target for inflammatory diseases.
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