Extracellular Vesicles in Synovial Fluid from Rheumatoid Arthritis Patients Contain miRNAs with Capacity to Modulate Inflammation
In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by...
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Published in | International journal of molecular sciences Vol. 22; no. 9; p. 4910 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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01.05.2021
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Abstract | In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high (n = 7)- or low (n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid (p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology. |
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AbstractList | In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high (n = 7)- or low (n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid (p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology. In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high ( n = 7)- or low ( n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid ( p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology. |
Author | Smyth, Gordon K Pang, Ken C Hill, Andrew F Foers, Andrew D Garnham, Alexandra L Cheng, Lesley Chatfield, Simon Wicks, Ian P |
AuthorAffiliation | 7 Department of Paediatrics, University of Melbourne, Parkville 3052, Australia 8 Department of Adolescent Medicine, Royal Children’s Hospital, Parkville 3052, Australia 1 The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; andrew.foers@kennedy.ox.ac.uk (A.D.F.); garnham.a@wehi.edu.au (A.L.G.); simon.chatfield@mh.org.au (S.C.); smyth@wehi.edu.au (G.K.S.) 6 Murdoch Children’s Research Institute, Parkville 3052, Australia 3 Department of Rheumatology, Royal Melbourne Hospital, Parkville 3050, Australia 5 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3086, Australia; L.Cheng@latrobe.edu.au (L.C.); Andrew.Hill@latrobe.edu.au (A.F.H.) 2 Department of Medical Biology, University of Melbourne, Parkville 3052, Australia 4 School of Mathematics & Statistics, University of Melbourne, Parkville 3010, Australia |
AuthorAffiliation_xml | – name: 8 Department of Adolescent Medicine, Royal Children’s Hospital, Parkville 3052, Australia – name: 1 The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; andrew.foers@kennedy.ox.ac.uk (A.D.F.); garnham.a@wehi.edu.au (A.L.G.); simon.chatfield@mh.org.au (S.C.); smyth@wehi.edu.au (G.K.S.) – name: 3 Department of Rheumatology, Royal Melbourne Hospital, Parkville 3050, Australia – name: 4 School of Mathematics & Statistics, University of Melbourne, Parkville 3010, Australia – name: 5 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3086, Australia; L.Cheng@latrobe.edu.au (L.C.); Andrew.Hill@latrobe.edu.au (A.F.H.) – name: 7 Department of Paediatrics, University of Melbourne, Parkville 3052, Australia – name: 6 Murdoch Children’s Research Institute, Parkville 3052, Australia – name: 2 Department of Medical Biology, University of Melbourne, Parkville 3052, Australia |
Author_xml | – sequence: 1 givenname: Andrew D. orcidid: 0000-0002-5036-7906 surname: Foers fullname: Foers, Andrew D. – sequence: 2 givenname: Alexandra L. surname: Garnham fullname: Garnham, Alexandra L. – sequence: 3 givenname: Simon surname: Chatfield fullname: Chatfield, Simon – sequence: 4 givenname: Gordon K. orcidid: 0000-0001-9221-2892 surname: Smyth fullname: Smyth, Gordon K. – sequence: 5 givenname: Lesley surname: Cheng fullname: Cheng, Lesley – sequence: 6 givenname: Andrew F. orcidid: 0000-0001-5581-2354 surname: Hill fullname: Hill, Andrew F. – sequence: 7 givenname: Ian P. surname: Wicks fullname: Wicks, Ian P. – sequence: 8 givenname: Ken C. orcidid: 0000-0002-6881-775X surname: Pang fullname: Pang, Ken C. |
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Immunol. doi: 10.1038/ni.3691 contributor: fullname: Villarino |
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Snippet | In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction.... |
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SubjectTerms | Apoptosis Arthritis Attenuation Cell growth Cytokines Extracellular vesicles Gene expression Genes Inflammation Interleukin 6 Joint diseases Joints (anatomy) MicroRNAs miRNA Oxygen enrichment Pathophysiology Patients Proteins Reactive oxygen species Rheumatoid arthritis RNA polymerase Signal transduction Size exclusion chromatography Stat3 protein Synovial fluid Transcription Vesicles |
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Title | Extracellular Vesicles in Synovial Fluid from Rheumatoid Arthritis Patients Contain miRNAs with Capacity to Modulate Inflammation |
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