Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47

• Published in: Scientific reports Vol. 6; no. 1; p. 19684
• Main Authors: Stein, Erica V, Miller, Thomas W, Ivins-O'Keefe, Kelly, Kaur, Sukhbir, Roberts, David D
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.01.2016
• Subjects: Adenosine Triphosphate - metabolism; Animals; Caspase 1 - genetics; Caspase 1 - metabolism; CD47 Antigen - genetics; CD47 Antigen - metabolism; Cell Line; Gene Expression; Humans; Interleukin-1beta - biosynthesis; Lipopolysaccharide Receptors - metabolism; Lipopolysaccharides - immunology; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Knockout; Models, Biological; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Protein Binding; Signal Transduction; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Toll-Like Receptor 4 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19684

Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1β, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia.