LncRNA HOTTIP from synovial fibroblast-derived exosomes: A novel molecular target for rheumatoid arthritis through the miR-1908-5p/STAT3 axis.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammation mediated by autoimmune responses. HOTTIP, a long noncoding RNA (lncRNA), participates in cell proliferation and invasion. However, the correlation between HOTTIP and RA remains unclear. Therefore, this study aimed to clarify how HOTTIP works in RA and to investigate its role in the development of RA. Flow cytometry was used to analyze cell cycle progression. Binding between HOTTIP, signal transducer and activator of transcription 3 (STAT3) and miR-1908-5p was demonstrated by dual-luciferase assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of T cell differentiation-related proteins. We found that HOTTIP was upregulated in rheumatoid arthritis synovial fibroblasts (RASFs). HOTTIP directly bound to miR-1908-5p and negatively modulated miR-1908-5p expression while positively regulating STAT3. The effects of HOTTIP overexpression on regulating the balance of the Th17/Treg cell ratio were partly reversed by miR-1908-5p overexpression. In addition, in vivo experiments demonstrated that overexpression of HOTTIP aggravated inflammation in RA mice, which was demonstrated by hematoxylin and eosin (HE) staining and the increased expression levels of CD4+ interleukin (IL)-17+, forkhead Box P3 (FOXP3) and retinoid-related orphan receptor gamma-t (RORγt). In summary, our study suggests that HOTTIP plays a damaging role in RA by promoting inflammation, which may be related to the regulation of miR-1908-5p expression and the STAT3 signaling pathway. These results suggest that the regulation of HOTTIP may be a promising therapeutic strategy for RA.

• Authors: Xueming Yao, Qiuyi Wang, Ping Zeng, Lei Hou, Yutao Yang, Daoming Lu, Ying Huang, Qiaoyi Ning, Hui Xu, Yuepeng Cao, Fang Tang, Yang An, Jing Zhou, Weichen Huang, Wukai Ma
• Journal: Experimental cell research (Exp Cell Res) Vol. 409 Issue 2 Pg. 112943 (12 15 2021) ISSN: 1090-2422 [Electronic] United States
• PMID: 34808131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• MicroRNAs
• RNA, Long Noncoding
• STAT3 Transcription Factor
• Stat3 protein, mouse

Topics

• Animals
• Apoptosis
• Arthritis, Experimental (etiology, metabolism, pathology)
• Arthritis, Rheumatoid (etiology, metabolism, pathology)
• Cell Proliferation
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Exosomes (genetics)
• Fibroblasts (metabolism, pathology)
• Mice
• MicroRNAs (genetics)
• RNA, Long Noncoding (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Synoviocytes (metabolism, pathology)