IRF-8/miR-451a regulates M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development

Guoping Shi,Dan Li,Dongya Zhang,Xiaoyu Xia,Li Lu,Yujun Xu,Yuchen Pan,Jingman Li,Huan Dou,Yayi Hou

doi:10.1038/s41420-021-00568-z

Guoping Shi, Dan Li + Show 8 more

Open Access

https://doi.org/10.1038/s41420-021-00568-z

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Abstract

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Myeloid-derived suppressor cells (MDSCs) have been found to be involved in the regulation of SLE development. However, little is known about the association between MDSC subsets and the factors that draw MDSCs into abnormal expansion. This study found that the percentage of M-MDSCs increased in mice with pristane-induced lupus. Toll-like receptor (TLR)7 signal activation and high interferon-α (IFN-α) level promoted M-MDSC differentiation in vitro. Moreover, both AMP-activated protein kinase (AMPK) agonist metformin and two mammalian targets of rapamycin (mTOR) inhibitors (INK128 and rapamycin) inhibited the percentage of M-MDSCs in lupus mice as well as in the TLR7- and IFN-α-induced bone marrow (BM) differentiation into MDSCs in vitro. In terms of mechanism, whole-genome transcriptome profiling was performed by RNA sequencing, revealing that the expression of the transcription factor IRF-8 was higher in M-MDSCs isolated from pristane-induced lupus mice, compared with control mice. IRF-8 was identified to be crucial for TLR7- and IFN-α-induced BM differentiation into MDSCs in vitro. Furthermore, interferon (IFN) regulatory factor8 (IRF-8) was targeted by miR-451a in M-MDSC differentiation. Of note, metformin-modified M-MDSCs could relieve lupus symptoms in pristane-induced lupus mice. The findings revealed a novel mechanism linking IRF-8/miR-451a to M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development. This study might provide an important reference for SLE therapy by targeting M-MDSCs.

Highlights

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by ubiquitous autoantibody production, immune complex deposition, multiple-organ dysfunction, and aberrant tissue inflammation [1]
On metformin-treated mice with lupus showed a better effect on assaying the percentage of M-myeloid-derived suppressor cells (MDSCs) in CD11b+ myeloid cells, we glomerulonephritis and infiltration of lymphocytes compared with found that the percentage of M-MDSCs was elevated in bone marrow (BM)
The number of G-MDSCs elevated in male lupus-prone (NZB × NZW) F1 mice compared with age-matched female mice, directly suppressing B-cell activation and differentiation in vitro [14]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by ubiquitous autoantibody production, immune complex deposition, multiple-organ dysfunction, and aberrant tissue inflammation [1]. Hormonal, and genetic factors play important roles during the development of SLE [2, 3]. Pristane (tetramethylpentadecane)-induced lupus is a murine model of SLE, facilitating research into the role of environmental factors in autoimmunity [4]. This murine lupus model is quite suitable for examining the links between dysregulated IFN-I production and the pathogenesis of human SLE. An increasing body of evidence suggests that early innate immune cells are highly important in the development of immunemediated inflammation in SLE [5, 6]. Till 2010, the abnormalities of myeloid-derived suppressor cells (MDSCs) were found to be involved in the regulation of the innate immune response in autoimmune disorders [11]

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