A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

Blood. 2016 Mar 3;127(9):1085-96. doi: 10.1182/blood-2015-05-644260. Epub 2015 Dec 8.

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.

Publication types

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

MeSH terms

  • 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

Substances

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