Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

Wang, Liping; Wang, Chunyan; Jia, Xuqiang; Yu, Jing

doi:10.1159/000494793

Cited by 62 publications

(33 citation statements)

References 19 publications

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“…This suggests that synovial tissue may regulate chondrocytes by secreting exosomes. Number of articles [15][16][17][18][19][20][21][22] has conducted detailed studies on how to extract cell supernatants and exosomes in body fluids, but few of articles had studied the extraction and identification of exosomes in tissues. To the best of our knowledge, any article has been published on how to extract and identify exosomes from synovial tissue.…”

Section: Introductionmentioning

confidence: 99%

Extraction and identification of synovial tissue-derived exosomes by different separation techniques

et al. 2020

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Objective: The aim of this study is to compare the efficiency of different separation techniques for extracting synovial tissue-derived exosomes. Methods: The synovial tissue discarded during knee arthroscopy or total knee arthroplasty surgery was collected from the Third Affiliated Hospital of Beijing University of Chinese Medicine. Ultracentrifugation (UC), filtration combined with size exclusion chromatography (SECF), and 8% polyethylene glycol (PEG) were used to extract synovial tissue-derived exosomes. Transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA), and Western Blot (WB) were used to detect the morphology, particle size, and biomarker proteins (CD9, CD63, Flotillin-1, and calnexin) of exosomes. Results: The extracts of enriched round and discoid vesicles were successfully extracted with UC, SECF, and PEG. The results of TEM have shown that all three extraction methods can extract circular or elliptical vesicles with discand cup-shaped structures from the synovial tissue, with the diameter is about 30-150 nm. NTA suggested the main peaks of three groups of exosomes are around 100-120 nm, and the concentration of the three groups of exosomes was greater than 1 × 10 10 /ml. The results of WB showed that three positive protein markers (CD9, CD63, and Flotillin-1) were highly expressed in the suspension extracted by the three methods and low in the synovial tissue. However, the negative protein (calnexin) was highly expressed in synovial tissues and PEG group, while low in UC and SECF group. Conclusion: Morphology, particle size, and labeled protein marker detection confirmed that UC, SECF, and PEG can extract exosomes derived from synovial tissue; UC and SECF are more recommended for the extraction of synovial tissue-derived exosomes, which provides a methodological basis for studying the function and mechanism of synovial tissue exosomes in the future.

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Section: Introductionmentioning

confidence: 99%

Extraction and identification of synovial tissue-derived exosomes by different separation techniques

et al. 2020

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“…In PBMCs, miR-99b-5p down-regulates mTOR and RASSF4 genes, thereby inhibiting T cell apoptosis, and promoting T cell proliferation and inflammatory response . Up-regulation of miR-17 in RA exosomes inhibits the differentiation of T-reg by suppressing the expression of TGFB2 (Wang et al, 2018a). Interestingly, miR-21 level is decreased in circulating PBMCs (Dong et al, 2014) but increased in Vγ9Vδ2T cells (Guggino et al, 2018) in RA patients, which could be associated with the imbalance of Th17/T-reg cells.…”

Section: Mirna-mediated Innate and Adaptive Immune Cell Differentiatimentioning

confidence: 96%

“…Interestingly, the expression of miR-146a decreases in T-reg cells during high RA activity, leading to a proinflammatory phenotype in these cells caused by concomitant upregulation of its target STAT1 (Zhou et al, 2015a). High levels of miR-99b-5p , miR-361-5p (Romo-Garcia et al, 2019), and miR-17 (Wang et al, 2018a) contribute to enhanced T cell proliferation and differentiation, and inhibit apoptosis. In PBMCs, miR-99b-5p down-regulates mTOR and RASSF4 genes, thereby inhibiting T cell apoptosis, and promoting T cell proliferation and inflammatory response .…”

Section: Mirna-mediated Innate and Adaptive Immune Cell Differentiatimentioning

confidence: 99%

Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

Guo¹,

Chang²,

Xu³

et al. 2020

Preprint

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MicroRNAs (miRNAs) play crucial roles in the regulation of the transcriptome and development of diseases including cancer and autoimmune diseases, such as rheumatoid arthritis (RA). Currently, a comprehensive map, illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interaction with terminal cells, such as T cells, fibroblast-like synoviocytes (FLS), osteoblasts, and osteoclasts, is still missing. In this review, we provide a thorough summary of the roles of miRNAs in the susceptibility to pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA, and regulate target genes and pathways including the NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, and mTOR pathways. By regulating gene expression, miRNAs affect T cell differentiation to diverse cell types, including Th17 and T-reg cells, and thus constitute promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the novel opportunities to combine these with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) to provide accurate diagnosis and prognosis, especially for seronegative patients. Furthermore, we outline how functional genetic variants of miR-499 and miR-146a partly explain the unmet susceptibility to RA. Additionally, we review the evidence implicating miRNAs as promising biomarkers of efficiency, response, and resistance to disease-modifying anti-rheumatic drugs (DMRDs) and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

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“…Interestingly, the expression of miR-146a reduced in T-reg cells during high activity of RA, by targeting STAT1, resulting the proinflammatory phenotype of T-reg cells (36). Besides that, the high level of miR-99b-5p (40), miR-361-5p (45) and miR-17 (46) participated in enhancing T cell proliferation and differentiation, anti-apoptosis. miR-99b-5p in peripheral blood mononuclear cells (PBMCs) was found to decrease the expression of mTOR and RASSF4 genes to inhibit T cell apoptosis, promoted T cell proliferation and inflammatory response (40).…”

Section: Mirnas Mediated Innate and Adaptive Immune Cell Differentiatmentioning

confidence: 99%

“…miR-99b-5p in peripheral blood mononuclear cells (PBMCs) was found to decrease the expression of mTOR and RASSF4 genes to inhibit T cell apoptosis, promoted T cell proliferation and inflammatory response (40). Upregulation of miR-17 in RA exosomes could inhibit the differentiation of T-reg by inhibiting the expression of TGFB2 (46). miR-21 decreased in peripheral blood circulating PBMCs(47), while increased in Vγ9Vδ2T cells (48) in RA patients, which associated with the imbalance of Th17/T-reg cells.…”

Section: Mirnas Mediated Innate and Adaptive Immune Cell Differentiatmentioning

confidence: 99%

Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

Guo¹,

Chang²,

Xu³

et al. 2020

Preprint

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Contribution:micro-RNA (miRNA) has been demonstrated to play important roles in the transcriptome regulation and disease development including cancer and autoimmune disease such as rheumatoid arthritis. However, a comprehensive role of miRNAs in rheumatoid arthritis (RA) including immune system differentiation and interaction with terminal cells like T cells, fibroblast-like synoviocytes (FLS), osteoblast and osteoclast still unclear. In this review, we have provided a thorough summary on the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention and prognosis. We summarized the blood and cell-free miRNA biomarkers which provided novel opportunity to work together with rheumatoid factors (RF), anti-CCP to provide accurate diagnosis and prognosis especially for seronegative patients. Finally, miRNAs were showed as promising biomarker to indicate the DMRDS and immunotherapy efficiency, drug response and resistance. What's more, autotherapeutic effect of miRNA intervention provided promising to develop miRNA based rheumatoid arthritis drugs. Overall, current evidence supports miRNAs as the interesting targets to better understand the pathogenetic mechanism and therapeutic intervention of rheumatoid arthritis.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 April 2020 Abstract micro-RNA (miRNA) has been demonstrated to play important roles in the transcriptome regulation and disease development including cancer and autoimmune disease such as rheumatoid arthritis. However, a comprehensive map on how the mRNAs regulate transcripts, pathways, immune system differentiation and interaction with terminal cells like T cells, fibroblast-like synoviocytes (FLS), osteoblast and osteoclast still unknown. In this review, we have provided a thorough summary on the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention and prognosis. Numerous miRNAs were found abnormally expressed in rheumatoid arthritis relevant cells and regulated the target genes and pathways like NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, mTOR pathway. In addition, miRNA act as gene expression regulators affect the T cell differentiate to different cell types including Th17 and T-reg cells which provide promising gene therapy target to regulate immune systems in rheumatoid arthritis. We also summarized interesting diagnosis and prognosis roles of blood and cell-free based miRNAs which provided novel opportunity to work together with rheumatoid factors (RF), anti-CCP to provide accurate diagnosis and prognosis especially for seronegative patients. Furthermore, functional genetic variants in miR-499 and miR-146a explained part of missing susceptibility of rheumatoid arthritis. Finally, miRNAs were showed as promising biomarker to indicate the DMRDS and immunotherapy efficiency, drug response and resistance. What's more, autotherapeutic effect of miRNA intervention provided promising to develop miRNA based rheumatoid arthritis drugs. Overall, current evidence supports miRNAs as the inter...

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Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

Cited by 62 publications

References 19 publications

Extraction and identification of synovial tissue-derived exosomes by different separation techniques

Extraction and identification of synovial tissue-derived exosomes by different separation techniques

Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

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