A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

MP Motley, DH Madsen, HJ Jürgensen… - Blood, The Journal …, 2016 - ashpublications.org
MP Motley, DH Madsen, HJ Jürgensen, DE Spencer, R Szabo, K Holmbeck, MJ Flick…
Blood, The Journal of the American Society of Hematology, 2016ashpublications.org
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 CC chemokine
receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin …
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.
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