Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Invasive pannus is a characteristic pathological feature of RA. RA fibroblast-like synoviocytes (FLSs) are showed tumor-like biological characters that facilitate pannus generation. Importantly, it has been documented that extracellular vesicle (EVs) derived microRNAs have a vital role of angiogenesis in various immune inflammatory diseases. However, whether RA FLSs derived EVs can facilitate angiogenesis and the underlying mechanism is undefined. Herein, we aim to investigate the key role of RA FLSs derived EVs on angiogenesis in endothelial cells (ECs). We indicate that RA FLSs derived EVs promote ECs angiogenesis by enhancing migration and tube formation of ECs in vitro. Also, we confirm that RA FLSs derived EVs can significantly facilitate ECs angiogenesis with a matrigel angiogenesis mice model. In terms of the mechanisms, both RNAs and proteins in EVs play roles in promoting ECs angiogenesis, but the RNA parts are more fundamental in this process. By combining microRNA sequencing and qPCR results, miR-1972 is identified to facilitate ECs angiogenesis. The blockage of miR-1972 significantly abrogated the angiogenesis stimulative ability of RA FLSs derived EVs in ECs, while the overexpression of miR-1972 reversed the effect in ECs. Specifically, the p53 level is decreased, and the phosphorylated mTOR is upregulated in miR-1972 overexpressed ECs, indicating that miR-1972 expedites angiogenesis through p53/mTOR pathway. Collectively, RA FLSs derived EVs can promote ECs angiogenesis via miR-1972 targeted p53/mTOR signaling, targeting on RA FLSs derived EVs or miR-1972 provides a promising strategy for the treatment of patients with RA.

Fibroblast-like synoviocytes (FLSs) are the predominant effector cells in the pathological progression of rheumatoid arthritis (RA). Therefore, elucidating the underlying molecular mechanism of the biologic behaviors in RA-FLSs will be helpful in developing the potent targets for the treatment of RA. We have previously documented that the tumor-like biologic behaviors of RA-FLSs are exacerbated by urokinase-type plasminogen activator receptor (uPAR), a specifically up-regulated receptor in RA-FLSs.Here, we investigate the further mechanism of uPAR and clarify its function in RA-FLSs. We demonstrate that miR-221-3p positively correlates to uPAR and regulates uPAR level in RA-FLSs. Simultaneously, one long noncoding RNA, nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) is identified, which can predictively target miR-221-3p at three sites, indicating a strong possibility of being a competing endogenous RNA in RA-FLSs. Interestingly, NEAT1_1 and miR-221-3p can colocate in the nucleus and cytoplasm in RA-FLSs. Importantly, NEAT1_1 can act as a rheostat for the miR-221-3p/uPAR axis and the downstream JAK signaling. In line with the biologic function, NEAT1_1 negatively regulates the tumor-like characters, and cytokine secretions of RA-FLSs. Collectively, our data provide new insight into the mechanisms of NEAT1_1 in modulating RA-FLSs tumor-like behaviors. The targeting of NEAT1_1 and miR-221-3p/uPAR axis may have a promising therapeutic role in patients with RA.

Macrophages are an important component of the human immune system and play a key role in the immune response, which can protect the body against infection and regulate the development of tissue inflammation. Some studies found that macrophages can produce extracellular traps (ETs) under various conditions of stimulation. ETs are web-like structures that consist of proteins and DNA. ETs are thought to immobilize and kill microorganisms, as well as play an important role in tissue damage, inflammatory progression, and autoimmune diseases. In this review, the structure, identification, mechanism, and research progress of macrophage extracellular traps (METs) in related diseases are reviewed.

BACKGROUND Altered phenotype of Fibroblast-like synoviocyte(FLS) is an important cause of the pathogenesis and progression of rheumatoid arthritis(RA) , but the speci c mechanism causing this change has not yet been fully explained. The exact mechanism by which the biological properties of FLS change in RA is still unclear. MiRNAs regulate the biological activity of FLS. Thus, we rst used miRNA microarray and WGCNA to con rm the RA-FLS miRNA landscape and establish their biological functions via network analyses at the system level, as well as to provide a platform for modulating the overall phenotypic effects of RA-FLS.METHODS We enrolled a total of 3 patients with RA and 3 healthy participants, constructed a network analysis of via miRNA microarray and RNA-sequencing. Furthermore, the coexpression analyses of miR-7 and ciRS-7 were veri ed by siRNA transfection, overexpression and qPCR analyses. Finally, we evaluated the effects of adjusting the expression levels of miR-7 and ciRS-7 on RA-FLS, respectively. RESULTS We identi ed distinct miRNA features in RA-FLS, including miR-7, which was signi cantly lower expressed. Furthermore, we discovered the negative regulatory relationship between ciRS-7 and miR-7 in RA-FLS. Finally, we overexpressed miR-7 in RA-FLS and discovered that miR-7 inhibited RA-FLS hyperproliferation, migration, invasion, and apoptosis, whereas ciRS-7 overexpression reversed these effects.CONCLUSION Our investigation identi ed that ciRS-7-miR-7 axis affects the tumor-like biological characters of RA-FLS. These ndings could aid in our understanding of essential roles of miR-7 in RA-FLS and will facilitate to development potential intervention target for RA.

OBJECTIVES: Electrocardiogram (ECG) abnormalities could predict some subsequent cardiovascular events. Cardiac involvement is a major extra-articular manifestation in rheumatoid arthritis (RA). We aimed to determine the prevalence of three major ECG abnormalities in RA patients, discover the associated ECG abnormalities associated with machine learning (ML) approaches, and then examine these preselected factors in the follow-up patients with traditional Cox regression. METHODS: Consecutive RA patients’ records were retrieved from the hospital database; about one-third of patients had follow-up data. Abnormal ECGs with clinical significance were grouped into non-specific ST-segment/T-wave changes, QT interval prolongation, and QRS-T angle increase. Machine learning approaches assessed the associated factors of these abnormalities. The top-important factors selected by the most optimal ML would be used to construct Cox regression models. RESULTS: Two hundred twenty-six patients were enrolled for the first step cross-sectional study. Non-specific ST-T changes (27%) were the most prevalent abnormalities among patients with abnormal ECGs. Random forest models had the best performance in the discovery of associated factors for three outcomes. Cox regression validated that rheumatoid factor and low-density lipoprotein were common risk factors within those three abnormalities. Hypertension, ESR, and serum immunoglobulin G were influential factors for non-specific ST-T changes, prolonged QT interval, and increased QRS-T angle specifically. CONCLUSION: Non-specific ST-T changes were the most common abnormalities seen in ECGs of RA patients. Our finding suggests that rheumatoid factor, LDL, hypertension, and inflammatory indicators are important risk factors for these ECG abnormalities.