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A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

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 and Thomas H. Bugge

Key points

  • Fibrin is cleared from extravascular space via endocytosis and lysosomal degradation by a CCR2-positive subset of inflammatory macrophages.

  • This novel endocytic fibrin degradation pathway is mechanistically coupled to extracellular fibrin degradation pathways.

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 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.

  • Submitted May 11, 2015.
  • Accepted November 30, 2015.