A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo.

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.

• Authors: Michael P Motley, Daniel H Madsen, Henrik J Jürgensen, David E Spencer, Roman Szabo, Kenn Holmbeck, Matthew J Flick, Daniel A Lawrence, Francis J Castellino, Roberto Weigert, Thomas H Bugge
• Journal: Blood (Blood) Vol. 127 Issue 9 Pg. 1085-96 (Mar 03 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26647393 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CX3C Chemokine Receptor 1
• Cx3cr1 protein, mouse
• Receptors, CCR2
• Receptors, Chemokine
• Receptors, Peptide
• fibrin receptor
• Fibrin
• Plasminogen
• Plasminogen Activators
• Fibrinolysin

Topics

• Animals
• Biological Assay
• CX3C Chemokine Receptor 1
• Cell Proliferation
• Endocytosis
• Fibrin (metabolism)
• Fibrinolysin (metabolism)
• Macrophages (metabolism)
• Mice
• Myeloid Cells (metabolism)
• Plasminogen (metabolism)
• Plasminogen Activators (metabolism)
• Proteolysis
• Receptors, CCR2 (metabolism)
• Receptors, Chemokine (metabolism)
• Receptors, Peptide (metabolism)