title: M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway.
abstract: Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase-dependent manner and was subsequently routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Col1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation of the collagen receptors mannose receptor (Mrc1) and urokinase plasminogen activator receptor-associated protein (Endo180 and Mrc2) impaired this intracellular collagen degradation pathway. This study demonstrates the importance of receptor-mediated cellular uptake to collagen turnover in vivo and identifies a key role of M2-like macrophages in this process.
authors.affiliation: Proteases and Tissue Remodeling Section and 2 Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, and 3 Matrix Metalloproteinase Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Madsen
authors.forename: Daniel
authors.initials: D
authors.lastname: Leonard
authors.forename: Andrius
authors.initials: A
authors.lastname: Masedunskas
authors.forename: Amanda
authors.initials: A
authors.lastname: Moyer
authors.forename: Henrik Jessen
authors.initials: HJ
authors.lastname: Jürgensen
authors.forename: Diane E
authors.initials: DE
authors.lastname: Peters
authors.forename: Panomwat
authors.initials: P
authors.lastname: Amornphimoltham
authors.forename: Arul
authors.initials: A
authors.lastname: Selvaraj
authors.forename: Susan S
authors.initials: SS
authors.lastname: Yamada
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
authors.forename: Lars H
authors.initials: LH
authors.lastname: Engelholm
authors.forename: Niels
authors.initials: N
authors.lastname: Behrendt
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000502:physiology*; D000090602:Collagen Type I, alpha 1 Chain; D004705:Endocytosis / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000073883:CX3C Chemokine Receptor 1; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C471885:Cx3cr1 protein, mouse; C581013:MRC1 protein, mouse; D008562:Membrane Glycoproteins; C474081:Mrc2 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D049452:Green Fluorescent Proteins; D003094:Collagen
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