title: A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo.
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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: Michael P
authors.initials: MP
authors.lastname: Motley
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD; Center for Cancer Immune Therapy, Department of Haematology, Herlev University Hospital, Herlev, Denmark; Finsen Laboratory, Biotech Research and Innovation Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Madsen
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD; Finsen Laboratory, Biotech Research and Innovation Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Jürgensen
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: David E
authors.initials: DE
authors.lastname: Spencer
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: Roman
authors.initials: R
authors.lastname: Szabo
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Division of Cardiovascular Medicine, Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; and.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: W. M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD;
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D001681:Biological Assay; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D004705:Endocytosis; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D059748:Proteolysis; D054390:Receptors, CCR2 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018000:Receptors, Peptide; C035637:fibrin receptor; D005337:Fibrin; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin