Mesenchymal stem cell-originated exosomal lncRNA HAND2-AS1 impairs rheumatoid arthritis fibroblast-like synoviocyte activation through miR-143-3p/TNFAIP3/NF-κB pathway

Abstract

Background Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown. Methods The expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot. Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays. The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay. The level of phosphorylated-p65 was examined by Western blot. The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Results HAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway. Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p. Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown. HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs. Conclusion MSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.

A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

“…Moreover, the expression rates of the TNFAIP3 gene have a negative association with the RA score, anti‑cyclic citrullinated peptide (CCP) antibody, and also CRP levels [ 127 ]. Correspondingly, a study showed that long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1)-abundant MSCs- exosomes inhibited the proliferation, migration, and inflammation and also exerted the apoptosis in RA-FLS cells by the suppression of the NF-κB pathway [ 128 ]. The central role of TNFAIP3 in the regulation of the NF-κB axis was elucidated when Lee et al supposed that TNFAIP3 − / − mice quickly expired because of the systemic inflammation elicited by spontaneously activated NF-κB [ 129 ].…”

Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis

“…miR-222-3p/Sirt1 axis is also found to be critical for the function of lncRNA GAS5 in mitigating the proliferation, inflammation, and apoptosis of RA FLS (289). In particular, lncRNA NEAT1 and lncRNA HAND2-AS1 are found in PBMC and mesenchymal stem cells (MSC), respectively, and are involved in the regulation of RA (241,255).…”

Cell-based therapies for rheumatoid arthritis: opportunities and challenges

“… 60 In RA, MSC-derived exosomes are found to inhibit the activation of FLS, cells that exert a key role on the progression of RA, through miR-143-3p/TNFAIP3/NF-κB pathway, emphasizing the vital role of TNFAIP3. 61 Moreover, hypoxia-inducible factor 1α (HIF1α) is a metabolic regulator required for MSC. Silencing of HIF1α in MSC is found to increase the ratio of Th17/Tregs, associated with the metabolic alteration and reduced immunosuppressive mediators like ICAM, IL-6, and nitric oxide (NO).…”