期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2020.551681
关键词
rheumatoid arthritis; long non-coding RNA NEAT1; peripheral blood monouclear cells; exosomes; microRNA-23a; MDM2; SIRT6
资金
- National Natural Science Foundation of China [81302576, 81402936]
- Six Talent Peak Research Project in Jiangsu Province [2015-WSN-105]
- 333 Project of Jiangsu Province [BRA2020175]
- Jiangsu Province Youth Medical Talent Project [QNRC2016348]
- Key Talents of Science and Education in Yangzhou City in 13th Five-Year [ZDRC201881]
- Jiangsu Provincial Natural Science Foundation of China [BK20131234]
Emerging evidence has pointed out the importance of long non-coding RNAs (lncRNAs) in multiple diseases, the knowledge of rheumatoid arthritis (RA)-associated lncRNAs remains limited. In this present study, we aimed to elucidate the mechanism of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) from peripheral blood monouclear cell (PBMC)-derived exosomes (exos) on RA development by modulating the microRNA-23a (miR-23a)/murine double minute-2 (MDM2)/Sirtuin 6 (SIRT6) axis. RA was modeledin vivoby collagen induction in mice andin vitroby exposing fibroblast-like synoviocytes (FLSs) to lipopolysaccharide. Exos were isolated from human or mouse PBMCs, which were then were co-cultured with FLSs. Based on gain- and loss-of-function experiments, the cell proliferation and secretion of inflammatory factors were measured. LncRNA NEAT1 was found to be highly expressed in RA, and PBMCs-derived exos contributed to RA development by delivering lncRNA NEAT1. In lipopolysaccharide-induced FLSs, miR-23a inhibited the expression of MDM2, and overexpression of MDM2 partially rescued the inhibitory effect of miR-23a on FLS proliferation and inflammatory response. Mechanistically, MDM2 ubiquitination degraded SIRT6 in RA. LncRNA NEAT1 shuttled by PBMC-derived exos promoted FLS proliferation and inflammation through regulating the MDM2/SIRT6 axis. Furthermore,in vivoexperiments suggested that downregulated lncRNA NEAT1 shuttled by PBMC-derived exos or upregulated miR-23a impeded RA deterioration in mice. This study highlights that lncRNA NEAT1 shuttled by PBMC-derived exos contributes to RA development with the involvement of the miR-23a/MDM2/SIRT6 axis.
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