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Published on: December 15, 2017
Plasmin-mediated fibrinolysis enables macrophage migration in a murine model of inflammation
Lakmali Munasinghage Silva1,2, Andrew Gary Lum2, Collin Tran1
1Proteases and Tissue Remodeling Section and.
Abstract:
Efficient migration of macrophages to sites of inflammation requires cell surface-bound plasmin(ogen). Here, we investigated the mechanisms underlying the deficits of plasmin(ogen)-mediated macrophage migration in 2 models: murine thioglycollate-induced peritonitis and in vitro macrophage migration. As previously reported, macrophage migration into the peritoneal cavity of mice in response to thioglycollate was significantly impaired in the absence of plasminogen. Fibrin(ogen) deposition was noted in the peritoneal cavity in response to thioglycollate, with a significant increase in fibrin(ogen) in the plasminogen-deficient mice. Interestingly, macrophage migration was restored in plasminogen-deficient mice by simultaneous imposition of fibrinogen deficiency. Consistent with this in vivo finding, chemotactic migration of cultured macrophages through a fibrin matrix did not occur in the absence of plasminogen. The macrophage requirement for plasmin-mediated fibrinolysis, both in vivo and in vitro, was negated by deletion of the major myeloid integrin αMβ2-binding motif on the γ chain of fibrin(ogen). The study identifies a critical role of fibrinolysis in macrophage migration, presumably through the alleviation of migratory constraints imposed by the interaction of leukocytes with fibrin(ogen) through the integrin αMβ2 receptor.
Insights
Efficient macrophage migration relies on plasminogen, a protein crucial for breaking down fibrin. This study reveals that plasminogen deficiency impairs macrophage movement by increasing fibrin deposition, highlighting fibrinolysis
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Efficient migration of macrophages to inflammatory sites is essential for immune responses.
- Cell surface-bound plasmin(ogen) plays a critical role in facilitating macrophage migration.
- Deficits in plasmin(ogen)-mediated migration can impede immune cell function.
Purpose of the Study:
- To investigate the mechanisms behind impaired plasmin(ogen)-mediated macrophage migration.
- To elucidate the role of fibrin(ogen) and fibrinolysis in macrophage migration.
- To identify the specific molecular interactions involved in leukocyte-fibrin(ogen) engagement.
Main Methods:
- Utilized murine thioglycollate-induced peritonitis model.
- Performed in vitro macrophage migration assays through fibrin matrices.
- Investigated the impact of plasminogen and fibrinogen deficiency on migration.
- Assessed the role of the integrin αMβ2-binding motif on fibrin(ogen) using genetic modifications.
Main Results:
- Macrophage migration was significantly impaired in plasminogen-deficient mice.
- Increased fibrin(ogen) deposition was observed in the peritoneal cavity of plasminogen-deficient mice.
- Macrophage migration was restored in plasminogen-deficient mice by simultaneous fibrinogen deficiency.
- In vitro macrophage chemotactic migration through fibrin failed without plasminogen.
- Deletion of the αMβ2-binding motif on fibrin(ogen) negated the requirement for plasmin-mediated fibrinolysis.
Conclusions:
- Fibrinolysis is critical for efficient macrophage migration, both in vivo and in vitro.
- Macrophage migration is constrained by interactions with fibrin(ogen) via the integrin αMβ2 receptor.
- Plasminogen-mediated fibrinolysis alleviates these migratory constraints, facilitating immune cell movement.
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