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

Erica V Stein,Thomas W Miller,David D Roberts,Kelly Ivins-O’Keefe,Sukhbir Kaur

doi:10.1038/srep19684

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 -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.

Highlights

To assess the potential utility of CD47-targeted therapeutics in cancer, one must consider additional physiological and pathophysiological functions of CD47 that could result in detrimental side effects[7]
CD47 promotes LPS-dependent transcription of IL-1β, NLRP3, and caspase-1 mRNAs, but ligation of CD47 by TSP1 inhibits this signal one-dependent inflammatory response by disrupting the interaction between CD14 and CD47
CD47 plays a role in signal two-mediated production of mature IL-1β

Summary

Introduction

To assess the potential utility of CD47-targeted therapeutics in cancer, one must consider additional physiological and pathophysiological functions of CD47 that could result in detrimental side effects[7]. Endogenous TSP1 enhances the pathogenesis of systemic C. albicans infections in mice despite enhancing macrophage activation and PMN recruitment[24]. Ligation with a CD47-blocking antibody, in the presence of infectious E. coli, overcame inhibitory TSP1 signaling that prevented the maturation of immature dendritic cells into mature DCs that produce inflammatory cytokines[32]. This inhibitory CD47 signal was not affected by knockdown of SIRPα. Infiltration of CD68+ macrophages into liver tissue after ischemia/reperfusion injury was reduced in thbs1−/− and cd47−/− mice, suggesting that TSP1 signaling through CD47 controls macrophage recruitment or activation[34]. The ability of induced multipotent stem cells from cd[47] null mice to be reprogrammed into Mac2+ macrophages in the presence of M-CSF was increased[35]

Methods

Results

Conclusion