Dissertation

CD47 Regulates IL-1β Production and Activation

Stein, Erica V

2014

Overview

An effective inflammatory response requires a complex balance between pro- and anti-inflammatory signals. Acute inflammation is protective but must be limited to prevent a detrimental cytokine storm or chronic inflammation. IL-1β is a major potentiator of acute and chronic inflammatory pathologies. Pro-IL-1 β, the inactive precursor to mature IL-1β, is transcriptionally upregulated in response to one stimulus and activated via a cleavage event in response to a second stimulus. LPS is a TLR4-dependent activator of NFκB-dependent up-regulation of IL-1β transcription. ATP can promote canonical IL-1β activation and secretion into the extracellular space that is inflammasome-dependent. This two-step cascade provides tight regulation of inflammation. CD47 has been shown to be a critical regulator of inflammatory responses. By interacting with its soluble ligand thrombospondin-1 and its counter-receptor signal regulatory protein-α (SIRPα), CD47 modulates neutrophil, macrophage, dendritic, and T cell localization and activation. The diverse signaling pathways regulated by CD47 led to the hypothesis that CD47 mediates IL-1β mRNA expression levels, transcription, and activation. In the present studies, it was determined that CD47 can promote LPS-dependent IL-1β mRNA expression, canonical ATP-dependent inflammasome activation of pro-IL-1β, and IL-1β secretion. Binding of TSP1 to CD47 supports CD47-dependent pro-IL-1β maturation. Although association with CD47 is sufficient for TSP1 to promote maturation of pro-IL-1β, it is not necessary because two other domains of TSP1 also induce pro-IL-1β maturation. Alternatively, in the presence of normal physiological levels of TSP1, CD47-induced LPS-dependent IL-1β transcription is inhibited. CD47 and CD14 associate with each other in lipid rafts. The CD47-binding domain of TSP1 specifically disrupts the interaction of CD14 with CD47. TSP1 thereby inhibits LPS-dependent activation of NFκB/AP-1 transcriptional activity and reduces induction of IL-1β message by LPS. Since IL-1β is essential in controlling and containing infection, we evaluated the role of CD47 in Candida albicans-dependent IL-1β transcription, activation and maturation. We found that at low infection rates, CD47 promoted C. albicans-induced IL-1β mRNA expression, activation of pro-IL-1β, and IL-1β secretion. However, at higher fungal burdens CD47 inhibits all these processes indicating that CD47's bimodal activities result from infection severity. Thus, these data show that CD47 can alter IL-1β transcription, maturation of pro-IL- β, and plays a possible role in inflammasome interactions. Therapeutic CD47 blocking drugs are currently under development to treat cancer, but the present results suggest that blocking CD47 signaling could compromise the IL-1β pro-inflammatory cascade that is vital for controlling microbial infections. CD47-targeted therapies, therefore, could impair the ability of immunocompromised cancer patients to resist and survive disseminated infections caused by C. albicans and other opportunistic pathogens.

• Publisher: ProQuest Dissertations & Theses
• Subject: Immunology / Microbiology / Oncology
• ISBN: 1321144296, 9781321144291