IRF-8/miR-451a regulates M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development.
Guoping ShiDan LiDongya ZhangYujun XuYuchen PanLi LuJingman LiXiaoyu XiaHuan DouYayi HouPublished in: Cell death discovery (2021)
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.
Keyphrases
- systemic lupus erythematosus
- disease activity
- toll like receptor
- dendritic cells
- immune response
- cell proliferation
- high glucose
- diabetic rats
- transcription factor
- rheumatoid arthritis
- protein kinase
- bone marrow
- drug induced
- inflammatory response
- single cell
- high fat diet induced
- skeletal muscle
- endothelial cells
- nuclear factor
- insulin resistance
- long non coding rna
- genome wide
- gene expression
- dna methylation
- oxidative stress
- cell therapy
- induced apoptosis
- cell death
- drug delivery
- binding protein
- signaling pathway