IRF8/miR-451a Regulates M-MDSC Differentiation via the AMPK/mTOR Signal Pathway During Lupus Development

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 M-MDSCs increased in mice with pristane-induced lupus. Toll-like receptor (TLR)7 signal activation and high IFN-α level promoted M-MDSC accumulation in vitro. Moreover, both AMPK agonist metformin and two mTOR inhibitors INK128 and rapamycin inhibited the percentage of M-MDSCs in mice with pristane-induced lupus 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 mice with pristane-induced lupus compared with control mice. IRF-8 was identified to be crucial for TLR7- and IFN-α-induced BM differentiation into MDSCs in vitro. Furthermore, IRF-8 was targeted by miR-451a in M-MDSC differentiation. Of note, metformin-modified M-MDSCs could relieve lupus symptoms in mice with pristane-induced lupus. The findings revealed a novel mechanism linking IRF8/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. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 31872732, 31570909), the Fundamental Research Funds of the Central Universities (No. 021414380342) and the Fund of State Key Laboratory of Trauma, Burns and Combined Injury (No. SKLKF201602). Declaration of Interests: The authors declare no commercial or financial conflicts of interest. Ethics Approval Statement: All procedures involving mice were approved by the institutional license for animal care and use based on the Animal Care Committee at Nanjing University.