Delivery of Long Non-coding RNA NEAT1 by Peripheral Blood Monouclear Cells-Derived Exosomes Promotes the Occurrence of Rheumatoid Arthritis via the MicroRNA-23a/MDM2/SIRT6 Axis.

Yujun Rao,Dan Liu,Yuxuan Fang,Wei Tan,Yubin Pang,Xia Wu,Guoqing Li,Chunwang Zhang

doi:10.3389/fcell.2020.551681

Abstract

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 modeled in vivo by collagen induction in mice and in vitro by 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 vivo experiments 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.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease featured by chronic inflammation, persistent synovitis, and destruction of synovial joints (Scott et al, 2010)
To further investigate the action of long non-coding RNAs (lncRNAs) nuclear paraspeckle assembly transcript 1 (NEAT1) on rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) were isolated from mice and co-cultured with exos derived from peripheral blood monouclear cell (PBMC), followed by cell viability assessment, secretion of inflammatory factors in the supernatants and p-p65 quantification
We found that lncRNA NEAT1 was upregulated in RA and PBMC-derived exos resulted in RA by delivering lncRNA NEAT1

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease featured by chronic inflammation, persistent synovitis, and destruction of synovial joints (Scott et al, 2010). The treatments for RA mainly focus on the immune system, inflammatory signaling pathways, and mediators (e.g., cytokines, kinases, proteases, and adhesion molecules implicated in the destructive process of the joints) (Oliveira and Fierro, 2018). Despite advances in these treatment approaches, the majority of patients with RA remain unremitted, it is urgent to elucidate the molecular mechanism of RA for the purpose of identifying the potential therapeutic targets for RA (Liang et al, 2019). A research has stated that the relative expression of miR-23a increased in psoriatic arthritis (PsA) compared to osteoarthritis (OA) (Wade et al, 2019)

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