title: OSCAR is a receptor for surfactant protein D that activates TNF-α release from human CCR2+ inflammatory monocytes.
abstract: Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2(+) inflammatory monocytes, which secreted TNF-α when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively colocalize in lung, as they were also highly expressed in atherosclerotic plaques of human aorta, supporting a role for this interaction in atherosclerosis. Our results identify the OSCAR:SP-D interaction as a potential therapeutic target in chronic inflammatory diseases of the lung as well as other diseases involving tissue accumulation of SP-D, infiltration of inflammatory monocytes, and release of TNF-α.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Barrow
authors.affiliation: Department of Cancer and Inflammation, University of Southern Denmark, 5000 Odense, Denmark;
authors.forename: Yaseelan
authors.initials: Y
authors.lastname: Palarasah
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, School of Medicine, University of Brescia, Brescia 25123, Italy;
authors.forename: Mattia
authors.initials: M
authors.lastname: Bugatti
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO 63110; Center for Biological Systems Engineering, Washington University, St. Louis, MO 63130; and.
authors.forename: Alex S
authors.identifier: http://orcid.org/0000-0002-4155-5729
authors.initials: AS
authors.lastname: Holehouse
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Byers
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Department of Molecular and Translational Medicine, Section of Pathology, School of Medicine, University of Brescia, Brescia 25123, Italy;
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.affiliation: Department of Cancer and Inflammation, University of Southern Denmark, 5000 Odense, Denmark;
authors.forename: Karsten
authors.initials: K
authors.lastname: Skjødt
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Erika
authors.initials: E
authors.lastname: Crouch
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; mcolonna@pathology.wustl.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019295:Computational Biology; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; C512828:OSCAR protein, human; D037663:Pulmonary Surfactant-Associated Protein D; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha