Upregulation of miR-210–5p impairs dead cell clearance by macrophages through the inhibition of Sp1-and HSCARG-dependent NADPH oxidase pathway

• Published in: Free radical biology & medicine Vol. 172; pp. 441 - 450
• Main Authors: Wu, Yi-Hsuan, Kuo, Chang-Fu, Hsieh, Ao-Ho, Hsieh, Hsi-Lung, Chan, Yen-Fan, Hwang, Tsong-Long
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2021
• Subjects: Dead cell clearance; Humans; Leukocytes, Mononuclear - metabolism; Lupus Erythematosus, Systemic; Macrophages - cytology; MicroRNAs - genetics; miR-210–5p; NADPH Oxidases - genetics; NOX signaling; Oxidoreductases; Sp1 Transcription Factor - genetics; Systemic lupus erythematosus; Transcription Factors - genetics; Up-Regulation; PBS; CGD; PhIx; miRNAs; PMA; HRP; SNECs; SLE; PBMCs; MFI; NOX signaling; Systemic lupus erythematosus; miR-210–5p; Dead cell clearance; NOX; ROS; PI
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.06.029

The deficiency of dead cell clearance is a prominent pathogenic factor in systemic lupus erythematosus (SLE). In this study, the overexpression of miR-210–5p resulted in the accumulation of secondary necrotic cells (SNECs) in macrophages through the reduction of protein degradation. The upreguation of miR-210–5p inhibited NADPH oxidase (NOX) activation, reactive oxygen species (ROS) generation, and SNEC clearance. miR-210–5p overexpression suppressed Sp1 and HSCARG expression, and the knockdown of SP1 and HSCARG inhibited NOX expression and superoxide production in macrophages. Furthermore, patients with active SLE expressed a higher level of miR-210–5p and lower expression of SP1 and HSCARG in peripheral blood mononuclear cells. In summary, our findings indicate that the upregulation of miR-210–5p increases the accumulation of SNECs through a decrease in the Sp1-and HSCARG-mediated NOX activity and ROS generation in macrophages. Our results also suggest that targeting miR-210–5p may have therapeutic potential for SLE. [Display omitted] •Patients with active SLE expressed a higher level of miR-210–5p in PBMCs.•Overexpression of miR-210–5p decreased superoxide generation and dead cell clearance in macrophages.•miR-210–5p impaired dead cell clearance through inhibiting SP1 and HSCARG-dependent NADPH oxidase pathway.