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A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo
Michael P Motley1, Daniel H Madsen2, Henrik J Jürgensen3
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
Abstract:
Extravascular fibrin deposition accompanies many human diseases and causes chronic inflammation and organ damage, unless removed in a timely manner. Here, we used intravital microscopy to investigate how fibrin is removed from extravascular space. Fibrin placed into the dermis of mice underwent cellular endocytosis and lysosomal targeting, revealing a novel intracellular pathway for extravascular fibrin degradation. A C-C chemokine receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin-uptaking cells. Consequently, cellular fibrin uptake was diminished by elimination of CCR2-expressing cells. The CCR2-positive macrophage subtype was different from collagen-internalizing M2-like macrophages. Cellular fibrin uptake was strictly dependent on plasminogen and plasminogen activator. Surprisingly, however, fibrin endocytosis was unimpeded by the absence of the fibrin(ogen) receptors, αMβ2 and ICAM-1, the myeloid cell integrin-binding site on fibrin or the endocytic collagen receptor, the mannose receptor. The study identifies a novel fibrin endocytic pathway engaged in extravascular fibrin clearance and shows that interstitial fibrin and collagen are cleared by different subsets of macrophages employing distinct molecular pathways.
Insights
Extravascular fibrin deposition is cleared via a novel intracellular pathway involving C-C chemokine receptor type 2 (CCR2)-positive macrophages. This process is essential for resolving inflammation and preventing organ damage in various diseases.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Extravascular fibrin deposition is a hallmark of numerous human diseases, contributing to chronic inflammation and organ damage.
- Efficient clearance of extravascular fibrin is crucial for tissue homeostasis and resolution of inflammatory processes.
Purpose of the Study:
- To investigate the cellular mechanisms and molecular pathways involved in the removal of extravascular fibrin.
- To identify the specific cell types responsible for fibrin clearance and the receptors mediating this process.
Main Methods:
- Intravital microscopy was employed to visualize fibrin degradation in the dermal space of mice.
- Flow cytometry and genetic manipulation were used to identify and characterize fibrin-uptaking cells, particularly macrophage subpopulations.
- Functional assays were performed to assess the dependence of fibrin uptake on specific molecular mediators.
Main Results:
- A novel intracellular pathway for extravascular fibrin degradation via cellular endocytosis and lysosomal targeting was identified.
- A distinct subpopulation of C-C chemokine receptor type 2 (CCR2)-positive macrophages was found to be the primary cell type responsible for fibrin uptake.
- Fibrin uptake by these macrophages was dependent on plasminogen and plasminogen activator but independent of αMβ2, ICAM-1, and the mannose receptor.
Conclusions:
- Extravascular fibrin clearance is mediated by a novel endocytic pathway involving CCR2-positive macrophages.
- This pathway represents a distinct mechanism from collagen clearance, which involves different macrophage subsets and molecular pathways.
- Understanding this fibrin clearance mechanism offers potential therapeutic targets for diseases associated with aberrant fibrin deposition.
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