MiR-155 Regulates IL-10-Producing CD24hiCD27+ B Cells and Impairs Their Function in Patients with Crohn's Disease.

Yingxia Zheng,Weiwei Wang,Wensong Ge,Yanhui Ma,Bingxian Bian,Lisong Shen,Li Han,Guohua Xie,Li Li

doi:10.3389/fimmu.2017.00914

Yingxia Zheng, Weiwei Wang + Show 7 more

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https://doi.org/10.3389/fimmu.2017.00914

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Abstract

Regulatory interleukin-10 (IL-10)-producing B cells (B10 cells) play a critical role in preventing and curing autoimmune diseases in experimental mouse models. However, the precise cellular and molecular mechanisms of action of B10 cells in humans, especially in patients with Crohn’s disease (CD), remain to be determined. miR-155 regulates many physiological and pathological conditions, including inflammation such as that in CD. In this study, we aimed to explore the effect of miRNA-155 on IL-10 production by B cells in healthy controls (HCs) and CD patients. Interestingly, we found that CD24hiCD27+ B cells express high levels of miRNA-155 and IL-10, which are positively correlated. Additionally, CD24hiCD27+ B cells express higher levels of Toll-like receptor 9 than those found in other B cell subsets. Overexpression of miRNA-155 promotes IL-10 production, while inhibition of miRNA-155 decreases IL-10 production. We determined that miR-155 directly inhibits the expression of Jarid2, which reduces H3K27me3 binding to the IL10 promoter and increases IL-10 gene expression. In coculture systems, the CD24hiCD27+ B cells from HCs suppressed the secretion of TNFα and IFNγ by monocytes and T cells, respectively. However, the number and function of CD24hiCD27+ B cells from CD patients were decreased. Moreover, we found that miR-155 induces CD24hiCD27+ B cells to produce higher levels of TNFα instead of IL-10 in CD patients than in the controls and that the increased number of IL-10+TNFα+ B cells reduces the induction of Foxp3 expression and the inhibition of IFNγ production by CD4+CD25− T cells, as well as TNFα production by monocytes. Our study demonstrates the critical role of miRNA-155 in the regulation of IL-10 production by B cells and reveals the novel molecular mechanism underlying the functional impairment of B10 cells in CD patients. Our study has the potential to drive the development of B10 cell-based strategies to ameliorate disease progression in CD patients.

Highlights

Many studies have conclusively demonstrated the significance of interleukin-10 (IL-10)-producing B cells (B10 cells) in diverse murine models and in human research on autoimmunity, infection, and cancer [1,2,3,4]
As reported by other studies, we found that the CD24hiCD27+ B cell subset produced higher levels of IL-10 after stimulation with CpG oligonucleotides for 48 h compared to those produced by other B cell subsets (Figure 1A)
These data were supported by the TLR9 expression measured in different B cells subsets (Figure 1B); the data show that the CD24hiCD27+ B cells, which are more sensitive to stimulation by CpG oligonucleotides, expressed higher levels of TLR9 than other B cell subsets

Summary

Introduction

Many studies have conclusively demonstrated the significance of interleukin-10 (IL-10)-producing B cells (B10 cells) in diverse murine models and in human research on autoimmunity, infection, and cancer [1,2,3,4]. Toll-like receptor (TLR) agonists, such as CpG oligonucleotides, potently induce B cells to produce IL-10 by activating STAT3 phosphorylation in human B cells [11]. A proliferation-inducing ligands promote the production and regulatory functions of IL-10 in human B cells [12]. IL-35 induces regulatory B cells to suppress autoimmune diseases [13]. The signaling pathways responsible for the development and function of B10 cells in humans are largely unknown; in particular, the roles of microRNAs (miRNAs) and chromatin regulators in these processes have not yet been demonstrated

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