Journal Article

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

Ivins-o'keefe, Kelly, Kaur, Sukhbir, Roberts, David D, Miller, Thomas W, Stein, Erica V

2016

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Bone marrow / Caspase / Caspase-1 / CD14 antigen / CD36 antigen / Cell activation / Cell surface / Endotoxemia / Inflammasomes / Inflammation / Interleukin 1 / Lipopolysaccharides / Macrophages / Monocytes / mRNA / NF-κB protein / Rodents / Thrombospondin / Transcription factors