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Research Article

miRNA-146a Improves Immunomodulatory Effects of MSC-derived Exosomes in Rheumatoid Arthritis

Author(s): Fataneh Tavasolian, Ahmad Zavaran Hosseini*, Sara Soudi and Mahmood Naderi

Volume 20, Issue 4, 2020

Page: [297 - 312] Pages: 16

DOI: 10.2174/1566523220666200916120708

Price: $65

Abstract

Background: Rheumatoid arthritis (RA) is a severe inflammatory joint disorder, and several studies have taken note of the probability that microRNAs (miRNAs) play an important role in RA pathogenesis. MiR-146 and miR-155 arose as primary immune response regulators. Mesenchymal stem cells (MSCs) immunomodulatory function is primarily regulated by paracrine factors, such as exosomes. Exosomes, which serve as carriers of genetic information in cell-to-cell communication, transmit miRNAs between cells and have been studied as vehicles for the delivery of therapeutic molecules.

Aims: The current research aimed to investigate the therapeutic effect of miR-146a/miR-155 transduced mesenchymal stem cells (MSC)-derived exosomes on the immune response.

Methods: Here, exosomes were extracted from normal MSCs with over-expressed miR-146a/miR-155; Splenocytes were isolated from collagen-induced arthritis (CIA) and control mice. Expression levels miR-146a and miR-155 were then monitored. Flow cytometry was performed to assess the impact of the exosomes on regulatory T-cell (Treg) levels. Expression of some key autoimmune response genes and their protein products, including retinoic acid-related orphan receptor (ROR)-γt, tumor necrosis factor (TNF)-α, interleukin (IL)-17, -6, -10, and transforming growth factor (TGF)-β in the Splenocytes was determined using both quantitative real-time PCR and ELISA. The results showed that miR-146a was mainly down-regulated in CIA mice. Treatment with MSC-derived exosomes and miR-146a/miR-155-transduced MSC-derived exosomes significantly altered the CIA mice Treg cell levels compared to in control mice.

Results: Ultimately, such modulation may promote the recovery of appropriate T-cell responses in inflammatory situations such as RA.

Conclusion: miR-146a-transduced MSC-derived exosomes also increased forkhead box P3 (Fox- P3), TGFβ and IL-10 gene expression in the CIA mice; miR-155 further increased the gene expressions of RORγt, IL-17, and IL-6 in these mice. Based on the findings here, Exosomes appears to promote the direct intracellular transfer of miRNAs between cells and to represent a possible therapeutic strategy for RA. The manipulation of MSC-derived exosomes with anti-inflammatory miRNA may increase Treg cell populations and anti-inflammatory cytokines.

Keywords: Mesenchymal stem cell, microRNA, exosomes, rheumatoid arthritis, autoimmune diseases, joints and bones.

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[1]
Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 2019; 15(1): 9-17.
[http://dx.doi.org/10.1038/s41584-018-0109-2] [PMID: 30341437]
[2]
Ai R, Laragione T, Hammaker D, et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun 2018; 9(1): 1921.
[http://dx.doi.org/10.1038/s41467-018-04310-9] [PMID: 29765031]
[3]
Mellado M, Martínez-Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM. T cell migration in rheumatoid arthritis. Front Immunol 2015; 6: 384.
[http://dx.doi.org/10.3389/fimmu.2015.00384] [PMID: 26284069]
[4]
Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int 2012; 32(9): 2731-6.
[http://dx.doi.org/10.1007/s00296-011-1984-x] [PMID: 21809006]
[5]
Abbasi M, Mousavi MJ, Jamalzehi S, et al. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol 2019; 234(7): 10018-31.
[http://dx.doi.org/10.1002/jcp.27860] [PMID: 30536757]
[6]
Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WW-Y. Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system. Ocul Surf 2016; 14(2): 121-34.
[http://dx.doi.org/10.1016/j.jtos.2015.11.004] [PMID: 26804815]
[7]
Tavasolian F, Moghaddam AS, Rohani F, et al. Exosomes: Effectual players in rheumatoid arthritis. Autoimmun Rev 2020; 19(6): 102511.
[http://dx.doi.org/10.1016/j.autrev.2020.102511] [PMID: 32171920]
[8]
Ferguson SW, Wang J, Lee CJ, et al. The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep 2018; 8(1): 1419.
[http://dx.doi.org/10.1038/s41598-018-19581-x] [PMID: 29362496]
[9]
Seo Y, Kim H-S, Hong I-S. Stem cell-derived extracellular vesicles as immunomodulatory therapeutics. Stem Cells Int 2019; 20195126156
[http://dx.doi.org/10.1155/2019/5126156] [PMID: 30936922]
[10]
Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol 2019; 20(1): 21-37.
[http://dx.doi.org/10.1038/s41580-018-0045-7] [PMID: 30108335]
[11]
Tavasolian F, Abdollahi E, Rezaei R, Momtazi-Borojeni AA, Henrotin Y, Sahebkar A. Altered expression of microRNAs in rheumatoid arthritis. J Cell Biochem 2018; 119(1): 478-87.
[http://dx.doi.org/10.1002/jcb.26205] [PMID: 28598026]
[12]
Maeda Y, Farina NH, Matzelle MM, Fanning PJ, Lian JB, Gravallese EM. Synovium‐derived microRNAs regulate bone pathways in rheumatoid arthritis. J Bone Miner Res 2017; 32(3): 461-72.
[http://dx.doi.org/10.1002/jbmr.3005] [PMID: 27676131]
[13]
Doody KM, Bottini N, Firestein GS. Epigenetic alterations in rheumatoid arthritis fibroblast-like synoviocytes. Epigenomics 2017; 9(4): 479-92.
[http://dx.doi.org/10.2217/epi-2016-0151] [PMID: 28322585]
[14]
Singh A, Patro PS, Aggarwal A. MicroRNA-132, miR-146a, and miR-155 as potential biomarkers of methotrexate response in patients with rheumatoid arthritis. Clin Rheumatol 2019; 38(3): 877-84.
[http://dx.doi.org/10.1007/s10067-018-4380-z] [PMID: 30511295]
[15]
Tavasolian F, Hosseini A Z, Soudi S, Naderi M, Sahebkar A. A systems biology approach for mirna-mrna expression patterns analysis in rheumatoid arthritis. Combin Chem High Throug Screen 2020.
[http://dx.doi.org/10.2174/1386207323666200605150024] [PMID: 32503403]
[16]
Wang D, Tang M, Zong P, et al. MiRNA-155 regulates the Th17/Treg ratio by targeting SOCS1 in severe acute pancreatitis. Front Physiol 2018; 9: 686.
[http://dx.doi.org/10.3389/fphys.2018.00686] [PMID: 29937734]
[17]
Wu Y-H, Liu W, Xue B, et al. Upregulated expression of microRNA-16 correlates with Th17/Treg cell imbalance in patients with rheumatoid arthritis. DNA Cell Biol 2016; 35(12): 853-60.
[http://dx.doi.org/10.1089/dna.2016.3349] [PMID: 27875659]
[18]
Testa U, Pelosi E, Castelli G, Labbaye C. miR-146 and miR-155: two key modulators of immune response and tumor development. Noncoding RNA 2017; 3(3): 22.
[http://dx.doi.org/10.3390/ncrna3030022] [PMID: 29657293]
[19]
Puno MR, Weick E-M, Das M, Lima CD. SnapShot: The RNA Exosome. Cell 2019; 179(1): 282-282.e1.
[http://dx.doi.org/10.1016/j.cell.2019.09.005] [PMID: 31539497]
[20]
Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noël D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep 2017; 7(1): 16214.
[http://dx.doi.org/10.1038/s41598-017-15376-8] [PMID: 29176667]
[21]
Takeuchi Y, Hirota K, Sakaguchi S. Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis. Immunol Rev 2020; 294(1): 164-76.
[http://dx.doi.org/10.1111/imr.12841] [PMID: 31944330]
[22]
Guo N, Ye S, Zhang K, et al. A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis. Cell Mol Immunol 2019; 16(6): 568-79.
[http://dx.doi.org/10.1038/s41423-018-0012-4] [PMID: 29563614]
[23]
Kondo Y, Yokosawa M, Kaneko S, et al. Transcriptional regulation of CD 4+ T cell differentiation in experimentally induced arthritis and rheumatoid arthritis. Arthritis Rheumatol 2018; 70(5): 653-61.
[http://dx.doi.org/10.1002/art.40398] [PMID: 29245178]
[24]
Osiri M, Wongpiyabovorn J, Sattayasomboon Y, Thammacharoenrach N. Inflammatory cytokine levels, disease activity, and function of patients with rheumatoid arthritis treated with combined conventional disease-modifying antirheumatic drugs or biologics. Clin Rheumatol 2016; 35(7): 1673-81.
[http://dx.doi.org/10.1007/s10067-016-3306-x] [PMID: 27188857]
[25]
Reyes-Pérez IV, Sánchez-Hernández PE, Muñoz-Valle JF, et al. Cytokines (IL-15, IL-21, and IFN-γ) in rheumatoid arthritis: association with positivity to autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) and clinical activity. Clin Rheumatol 2019; 38(11): 3061-71.
[http://dx.doi.org/10.1007/s10067-019-04681-4] [PMID: 31312989]
[26]
Lazzerini PE, Capecchi PL, Laghi-Pasini F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 2017; 38(22): 1717-27.
[PMID: 27252448]
[27]
Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis 2018; 77(2): 175-87.
[http://dx.doi.org/10.1136/annrheumdis-2017-211555] [PMID: 28765121]
[28]
Hu X-X, Wu YJ, Zhang J, Wei W. T-cells interact with B cells, dendritic cells, and fibroblast-like synoviocytes as hub-like key cells in rheumatoid arthritis. Int Immunopharmacol 2019; 70: 428-34.
[http://dx.doi.org/10.1016/j.intimp.2019.03.008] [PMID: 30856393]
[29]
Petralia MC, Mazzon E, Basile MS, et al. Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis. Pharmaceuticals (Basel) 2019; 12(4): 174.
[http://dx.doi.org/10.3390/ph12040174] [PMID: 31783688]
[30]
Araki Y, Mimura T. Matrix metalloproteinase gene activation resulting from disordred epigenetic mechanisms in rheumatoid arthritis. Int J Mol Sci 2017; 18(5): 905.
[http://dx.doi.org/10.3390/ijms18050905] [PMID: 28441353]
[31]
Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 2017; 542(7639): 110-4.
[http://dx.doi.org/10.1038/nature20810] [PMID: 28150777]
[32]
Tanaka S, Tanaka Y, Ishiguro N, Yamanaka H, Takeuchi T. RANKL: A therapeutic target for bone destruction in rheumatoid arthritis. Mod Rheumatol 2018; 28(1): 9-16.
[http://dx.doi.org/10.1080/14397595.2017.1369491] [PMID: 28880683]
[33]
Downey C. Serious infection during etanercept, infliximab and adalimumab therapy for rheumatoid arthritis: A literature review. Int J Rheum Dis 2016; 19(6): 536-50.
[http://dx.doi.org/10.1111/1756-185X.12659] [PMID: 26200188]
[34]
Bahardeeen Z. Anti-TNFα biologics in the pharmacotherapy of rheumatoid arthritis: effectiveness and safety of infliximab, adalimumab and etanercept. Int J Med Rev 2019; 6: 92-100.
[http://dx.doi.org/10.29252/IJMR-060305]
[35]
Kim K-W, Kim HJ, Kim B-M, Kwon Y-R, Kim H-R, Kim Y-J. Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on the Th17 responses of cells from rheumatoid arthritis patients. Stem Cell Res Ther 2018; 9(1): 208.
[http://dx.doi.org/10.1186/s13287-018-0948-4] [PMID: 30092847]
[36]
Tavasolian F, Hosseini AZ, Mirzaei A, et al. Unfolded protein response-mediated modulation of mesenchymal stem cells. IUBMB Life 2020; 72(2): 187-97.
[http://dx.doi.org/10.1002/iub.2154] [PMID: 31444957]
[37]
Melief SM, Schrama E, Brugman MH, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells 2013; 31(9): 1980-91.
[http://dx.doi.org/10.1002/stem.1432] [PMID: 23712682]
[38]
Zhang B, Yeo RWY, Lai RC, Sim EWK, Chin KC, Lim SK. Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway. Cytotherapy 2018; 20(5): 687-96.
[http://dx.doi.org/10.1016/j.jcyt.2018.02.372] [PMID: 29622483]
[39]
Pegtel DM, Peferoen L, Amor S. Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos Trans R Soc Lond B Biol Sci 2014; 369(1652): 20130516.
[http://dx.doi.org/10.1098/rstb.2013.0516] [PMID: 25135977]
[40]
Li J, Xue H, Li T, et al. Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE-/- mice via miR-let7 mediated infiltration and polarization of M2 macrophage. Biochem Biophys Res Commun 2019; 510(4): 565-72.
[http://dx.doi.org/10.1016/j.bbrc.2019.02.005] [PMID: 30739785]
[41]
Toh WS, Lai RC, Hui JHP, Lim SK. MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment Seminars in cell & developmental biology. Elsevier 2017; pp. 56-64.
[42]
Bruno S, Deregibus MC, Camussi G. The secretome of mesenchymal stromal cells: Role of extracellular vesicles in immunomodulation. Immunol Lett 2015; 168(2): 154-8.
[http://dx.doi.org/10.1016/j.imlet.2015.06.007] [PMID: 26086886]
[43]
Cosenza S, Toupet K, Maumus M, et al. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics 2018; 8(5): 1399-410.
[http://dx.doi.org/10.7150/thno.21072] [PMID: 29507629]
[44]
Ansboro S, Roelofs AJ, De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol 2017; 29(2): 201-7.
[http://dx.doi.org/10.1097/BOR.0000000000000370] [PMID: 27941390]
[45]
Maumus M, Jorgensen C, Noël D. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 2013; 95(12): 2229-34.
[http://dx.doi.org/10.1016/j.biochi.2013.04.017] [PMID: 23685070]
[46]
Hippen KL, Loschi M, Nicholls J, MacDonald KPA, Blazar BR. Effects of microRNA on regulatory T cells and implications for adoptive cellular therapy to ameliorate graft-versus-host disease. Front Immunol 2018; 9: 57.
[http://dx.doi.org/10.3389/fimmu.2018.00057] [PMID: 29445371]
[47]
Tang X, Tang R, Xu Y, et al. MicroRNA networks in regulatory T cells. J Physiol Biochem 2014; 70(3): 869-75.
[http://dx.doi.org/10.1007/s13105-014-0348-x] [PMID: 25108555]
[48]
Song Y, Dou H, Li X, et al. Exosomal miR‐146a contributes to the enhanced therapeutic efficacy of interleukin‐1β‐primed mesenchymal stem cells against sepsis. Stem Cells 2017; 35(5): 1208-21.
[http://dx.doi.org/10.1002/stem.2564] [PMID: 28090688]
[49]
Dong C, Zhou Q, Fu T, et al. Circulating exosomes derived-miR-146a from systemic lupus erythematosus patients regulates senescence of mesenchymal stem cells. BioMed Res Int 2019; 2019: 6071308.
[http://dx.doi.org/10.1155/2019/6071308] [PMID: 31428639]
[50]
Saba R, Sorensen DL, Booth SA. MicroRNA-146a: a dominant, negative regulator of the innate immune response. Front Immunol 2014; 5: 578.
[http://dx.doi.org/10.3389/fimmu.2014.00578] [PMID: 25484882]
[51]
Xu W-D, Lu M-M, Pan H-F, Ye D-Q. Association of MicroRNA-146a with autoimmune diseases. Inflammation 2012; 35(4): 1525-9.
[http://dx.doi.org/10.1007/s10753-012-9467-0] [PMID: 22535496]
[52]
Moghimi B, Gharibi S, Farashahi Yazd E, Taher Tahoori M, Kalantar SM. Role of miR-146a in immune system and autoimmunity. Int J Med Lab 2016; 3: 150-8.
[53]
Zhou Q, Haupt S, Kreuzer JT, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis 2015; 74(6): 1265-74.
[http://dx.doi.org/10.1136/annrheumdis-2013-204377] [PMID: 24562503]
[54]
Duan Q, Mao X, Xiao Y, et al. Super enhancers at the miR-146a and miR-155 genes contribute to self-regulation of inflammation. Biochim Biophys Acta 2016; 1859(4): 564-71.
[http://dx.doi.org/10.1016/j.bbagrm.2016.02.004] [PMID: 26855180]
[55]
Kriegsmann M, Randau TM, Gravius S, et al. Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial tissues of patients with rheumatoid arthritis and osteoarthritis. Virchows Arch 2016; 469(1): 93-100.
[http://dx.doi.org/10.1007/s00428-016-1939-4] [PMID: 27079198]
[56]
Magilnick N, Reyes EY, Wang W-L, et al. miR-146a-Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression. Proc Natl Acad Sci USA 2017; 114(34): E7140-9.
[http://dx.doi.org/10.1073/pnas.1706833114] [PMID: 28784800]
[57]
Su LC, Huang AF, Jia H, Liu Y, Xu WD. Role of microRNA-155 in rheumatoid arthritis. Int J Rheum Dis 2017; 20(11): 1631-7.
[http://dx.doi.org/10.1111/1756-185X.13202] [PMID: 29105307]
[58]
Elmesmari A, Fraser AR, Wood C, et al. MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis. Rheumatology (Oxford) 2016; 55(11): 2056-65.
[http://dx.doi.org/10.1093/rheumatology/kew272] [PMID: 27411480]
[59]
Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M. The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum 2011; 63(6): 1582-90.
[http://dx.doi.org/10.1002/art.30321] [PMID: 21425254]
[60]
Kurowska-Stolarska M, Alivernini S, Ballantine LE, et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci USA 2011; 108(27): 11193-8.
[http://dx.doi.org/10.1073/pnas.1019536108] [PMID: 21690378]
[61]
Yin Z, Luo X, Zhang C, Chen X, Huang J, Zhizhong Y. miR-155 facilitates the differentiation of Th17 cells by inhibiting the gene expression of Ets-1 Chinese. J Rheumatol 2015; 19: 730-4.
[http://dx.doi.org/10.1136/annrheumdis-2015-eular.4288]
[62]
Migita K, Iwanaga N, Izumi Y, et al. TNF-α-induced miR-155 regulates IL-6 signaling in rheumatoid synovial fibroblasts. BMC Res Notes 2017; 10(1): 403.
[http://dx.doi.org/10.1186/s13104-017-2715-5] [PMID: 28807007]
[63]
Ksiazek-Winiarek D, Szpakowski P, Turniak M, Szemraj J, Glabinski A. IL-17 exerts anti-apoptotic effect via miR-155-5p downregulation in experimental autoimmune encephalomyelitis. J Mol Neurosci 2017; 63(3-4): 320-32.
[http://dx.doi.org/10.1007/s12031-017-0981-2] [PMID: 29063445]
[64]
Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 2016; 12(1): 25-36.
[http://dx.doi.org/10.1038/nrrheum.2015.167] [PMID: 26633291]

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