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

Scientific Reports
Erica V SteinDavid D Roberts

Abstract

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 -indepe...Continue Reading

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Citations

Jul 18, 2017·Antioxidants & Redox Signaling·David D RobertsJeffrey S Isenberg
Oct 24, 2018·American Journal of Physiology. Endocrinology and Metabolism·Hasiyet MemetiminShuxia Wang
Nov 5, 2019·Investigative Ophthalmology & Visual Science·Samy OmriSylvain Chemtob
Mar 21, 2020·American Journal of Reproductive Immunology : AJRI·Yukai LiuXiaoyong Zhu
May 7, 2020·American Journal of Physiology. Cell Physiology·Jeffrey S Isenberg, David D Roberts
Feb 1, 2020·BMC Medical Genomics·Julius MulindwaChristine Clayton
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May 1, 2021·International Journal of Molecular Sciences·Sukhbir KaurDavid D Roberts
May 1, 2021·International Journal of Molecular Sciences·Atharva KaleKedar Ghimire
Jun 3, 2021·Cells·Jin Kyun ParkYeong Wook Song
May 14, 2020·Cell Reports·Verena RolfesBernardo Simoes Franklin

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Methods Mentioned

BETA
xenografts
ELISA
density-gradient centrifugation
Assay
PCR
PMA

Clinical Trials Mentioned

NCT02216409
NCT02367196
NCT02488811

Software Mentioned

GraphPad
Gen5

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