A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

TY - JOUR

T1 - A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

AU - Motley, Michael P

AU - Madsen, Daniel H.

AU - Jürgensen, Henrik J.

AU - Spencer, David E

AU - Szabo, Roman

AU - Holmbeck, Kenn

AU - Flick, Matthew J

AU - Lawrence, Daniel A

AU - Castellino, Francis J

AU - Weigert, Roberto

AU - Bugge, Thomas H

PY - 2016/3/3

Y1 - 2016/3/3

N2 - 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.

AB - 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.

KW - Animals

KW - Biological Assay

KW - CX3C Chemokine Receptor 1

KW - Cell Proliferation

KW - Endocytosis

KW - Fibrin/metabolism

KW - Fibrinolysin/metabolism

KW - Macrophages/metabolism

KW - Mice

KW - Myeloid Cells/metabolism

KW - Plasminogen/metabolism

KW - Plasminogen Activators/metabolism

KW - Proteolysis

KW - Receptors, CCR2/metabolism

KW - Receptors, Chemokine/metabolism

KW - Receptors, Peptide/metabolism

U2 - 10.1182/blood-2015-05-644260

DO - 10.1182/blood-2015-05-644260

M3 - Journal article

C2 - 26647393

SN - 0006-4971

VL - 127

SP - 1085

EP - 1096

JO - Blood

JF - Blood

IS - 9

ER -