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, Thomas H Bugge

33 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftBlood
Vol/bind127
Udgave nummer9
Sider (fra-til)1085-96
Antal sider12
ISSN0006-4971
DOI
StatusUdgivet - 3 mar. 2016

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