A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

作者：Motley Michael P; Madsen Daniel H; Jurgensen Henrik J; Spencer David E; Szabo Roman; Holmbeck Kenn; Flick Matthew J; Lawrence Daniel A; Castellino Francis J; Weigert Roberto; Bugge Thomas H^*

来源：Blood, 2016, 127(9): 1085-1096.

DOI：10.1182/blood-2015-05-644260

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, aMb2 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.

• 出版日期2016-3-3
• 单位NIH