title: Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury.
abstract: Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin (TSP)-1 (thbs1⁻/⁻), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to lipopolysaccharide-induced lung injury and show defective macrophage interleukin (IL)-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1⁻/⁻ mice from persistent neutrophilic lung inflammation and injury and thbs1⁻/⁻ alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co-culture with apoptotic neutrophils, thbs1⁻/⁻ macrophages show a selective defect in IL-10 production, whereas prostaglandin E2 and transforming growth factor beta 1 responses remain intact. Full macrophage IL-10 responses require the engagement of TSP-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lechner
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Klenotic
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Hamburg
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hulver
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Khare
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: T
authors.initials: T
authors.lastname: Oriss
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mangalmurti
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chan
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Ross
authors.affiliation: Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Rosengart
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pilewski
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ray
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: 1] Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000172:deficiency; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000009:adverse effects; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D008070:Lipopolysaccharides; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D015232:Dinoprostone
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