MiR-29b and miR-29c Are Involved in Toll-Like Receptor Control of Glucocorticoid-Induced Apoptosis in Human Plasmacytoid Dendritic Cells

Yongfeng Hong,Xianshan Shen,Yi Liu,Tianping Chen,Tianping Chen,Jianxian Wu,Jingpu Zhao,Xiuli Kan,Huiping Wang,Huiping Wang,Kaili Yan,Zhimin Zhai,Zhimin Zhai,Qianshan Tao,Qianshan Tao,Rolf Müller

doi:10.1371/journal.pone.0069926

Yongfeng Hong, Xianshan Shen + Show 14 more

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https://doi.org/10.1371/journal.pone.0069926

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Abstract

Glucocorticoids (GCs) are frequently used to treat many of the acute disease manifestations associated with inflammatory and autoimmune disorders. However, Toll-like receptor (TLR) pathway-activated plasmacytoid dendritic cells (pDCs) are resistant to GC-induced apoptosis, which leads to the inefficiency of GCs in the treatment of type I interferon-related autoimmune diseases, such as systemic lupus erythematosus (SLE). Therefore, compounds promoting pDC apoptosis may be helpful for improving the efficacy of GCs. In this study, we performed screening to identify microRNAs (miRNAs) involved in TLR-inhibited GC-induced pDC apoptosis and found an array of miRNAs that may regulate pDC apoptosis. Among those demonstrating altered expression, 6 miRNAs were inhibited in TLR-activated pDCs. Bioinformatics analysis and functional studies indicated that miR-29b and miR-29c were 2 key miRNAs involved in TLR-inhibited GC-induced pDC apoptosis. Furthermore, both of these miRNAs promoted pDC apoptosis by directly targeting Mcl-1 and Bcl-2 in human primary pDCs. Our findings provide new targets that could improve the efficacy of GCs for the treatment of SLE.

Highlights

Glucocorticoids (GCs) are small lipophilic compounds that mediate a plethora of biological effects by binding the intracellular glucocorticoid receptor (GR), which, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription [1]
To investigate the involvement of miRNAs in Toll-like receptor (TLR)-inhibited GC-induced Plasmacytoid dendritic cells (pDCs) apoptosis, human primary pDCs were treated with Dex alone or the combination of Dex and CpG for 16 hours. miRNA profiles were detected using miRNA microarrays (Figure 1)
What’s more, 6 miRNAs were up-regulated following Dex stimulation, while CpG prevented their induction (Figure S1).These results indicate that the identified miRNAs may be important for the anti-apoptotic effect of TLR stimulation in human primary pDCs during culture with GCs

Summary

Introduction

Glucocorticoids (GCs) are small lipophilic compounds that mediate a plethora of biological effects by binding the intracellular glucocorticoid receptor (GR), which, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription [1]. GCs have been shown to affect the viability of dendritic cells (DCs), to selectively down-regulate the expression of co-stimulatory molecules on viable DCs, and strongly reduce the immunostimulatory properties of DCs both in vitro and in vivo [2,3]. Because of their inhibitory effects on both acquired and innate immunological functions, GCs are remarkably efficacious in managing many of the acute disease manifestations of inflammatory and autoimmune disorders [1,2,3].

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