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Mucosal Immunol. 2014 Mar;7(2):440-8. doi: 10.1038/mi.2013.63. Epub 2013 Sep 18.

Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury.

Author information

1
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
2
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
3
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
4
Department of Cell Biology and Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
5
Division of Trauma Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
6
Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
7
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.

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.

PMID:
24045574
PMCID:
PMC3945733
DOI:
10.1038/mi.2013.63
[Indexed for MEDLINE]
Free PMC Article
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