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MicroRNA-155 acts as a potential prognostic and diagnostic factor in patients with ankylosing spondylitis by modulating SOCS3

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Abstract

Background

Ankylosing spondylitis (AS) is a progressive inflammatory disease. Our primary objective was to explore the role of miR-155 and its targeted factors in AS pathogenesis.

Methods and results

PBMCs were isolated from 30 AS patients and 30 healthy individuals using the Ficoll-hypaque isolation approach. The expression of miR-155 and its associated targets, including Suppressor Of Cytokine Signaling 3 (SOCS3), STAT3, and IL-21, were determined using qT-qPCR. Then, PBMCs were cultured, and the effect of miR-155, SOCS3 siRNA (to suppress its expression), pEFSOCS3 (enforced expression), and their combination were investigated by qRT-PCR and western blotting. We also treated the cultured PBMCs with Brefeldin A, a potent inhibitor of cytokine secretion, to determine its effect on IL-21 expression and secretion. In addition, the association between miR-155 and patients’ clinicopathological features was examined. The results showed that miR-155, IL-21, and STAT3 were increased in patients with AS, while SOCS3 had decreasing expression trend. It was also determined that miR-155 alleviates SOCS3 expression and increases IL-21 and STAT3 expression; it had a prominent effect when combined with SOCS3 siRNA. Besides, we showed that simultaneous transfection of miR-155 and pEFSOCS3 had no significant effect on IL-21 and STAT3 expression, revealing that miR-155 could alleviate the enforced expression of SOCS3. It was also proven that Brefledine A led to IL-21 up-regulation or accumulation while relieving its secretion. Also, a significant correlation between miR-155 and pathological features of AS patients was found.

Conclusion

miR-155 acts as a potential prognostic and diagnostic biomarker. Its up-regulation leads to the down-regulation of SOCS3 and increased expression of IL-21 and STAT3 as characteristic of TH-17 lymphocytes, leading to worsening inflammatory conditions in patients with AS.

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References

  1. Simone D, Al Mossawi MH, Bowness P (2018) Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/key001

    Article  Google Scholar 

  2. Voruganti A, Bowness P (2020) New developments in our understanding of ankylosing spondylitis pathogenesis. Immunology 161:94–102

    Article  CAS  Google Scholar 

  3. Bowness P (2015) HLA-B27. Annu Rev Immunol 33:29–48

    Article  CAS  Google Scholar 

  4. Hwang ES (2010) Transcriptional regulation of T helper 17 cell differentiation. Yonsei Med J 51:484–491

    Article  CAS  Google Scholar 

  5. Tateiwa D, Yoshikawa H, Kaito T (2019) Cartilage and bone destruction in arthritis: pathogenesis and treatment strategy: a literature review. Cells. https://doi.org/10.3390/cells8080818

    Article  Google Scholar 

  6. Nabipoorashrafi SA, Shomali N, Sadat-Hatamnezhad L et al (2020) MiR-143 acts as an inhibitor of migration and proliferation as well as an inducer of apoptosis in melanoma cancer cells in vitro. IUBMB Life 72:2034–2044

    Article  CAS  Google Scholar 

  7. Tamjidifar R, Akbari M, Tarzi S et al (2021) Prognostic and diagnostic values of miR-506 and SPON 1 in colorectal cancer with clinicopathological considerations. J Gastrointest Cancer 52:125–129

    Article  CAS  Google Scholar 

  8. Azar M, Aghazadeh H, Mohammed HN et al (2021) miR-193a-5p as a promising therapeutic candidate in colorectal cancer by reducing 5-FU and oxaliplatin chemoresistance by targeting CXCR4. Int Immunopharmacol 92:107355

    Article  CAS  Google Scholar 

  9. Ghaderian S, Shomali N, Behravesh S et al (2020) The emerging role of lncRNAs in multiple sclerosis. J Neuroimmunol 347:577347

    Article  CAS  Google Scholar 

  10. Shomali N, Hatamnezhad LS, Tarzi S et al (2021) Heat shock proteins regulating toll-like receptors and the immune system could be a novel therapeutic target for melanoma. Curr Mol Med 21:15–24

    Article  CAS  Google Scholar 

  11. Shomali N, Suliman Maashi M, Baradaran B et al (2022) Dysregulation of survivin-targeting microRNAs in autoimmune diseases: new perspectives for novel therapies. Front Immunol 13:839945

    Article  CAS  Google Scholar 

  12. Pashangzadeh S, Motallebnezhad M, Vafashoar F et al (2021) Implications the role of miR-155 in the pathogenesis of autoimmune diseases. Front Immunol 12:669382

    Article  CAS  Google Scholar 

  13. Liu ZQ, Feng J, Shi LL et al (2019) Influences of miR-155/NF-κB signaling pathway on inflammatory factors in ARDS in neonatal pigs. Eur Rev Med Pharmacol Sci 23:7042–7048

    Google Scholar 

  14. Chen M, Wang F, Xia H et al (2021) MicroRNA-155: regulation of immune cells in sepsis. Mediators Inflamm 2021:8874854

    Article  Google Scholar 

  15. Qian BP, Ji ML, Qiu Y et al (2016) Identification of serum miR-146a and miR-155 as novel noninvasive complementary biomarkers for ankylosing spondylitis. Spine 41:735–742

    Article  Google Scholar 

  16. Chakraborty R, Darido C, Alnakli AA et al (2022) A review on the dual role of SOCS3 in cancer. Res Oncol. https://doi.org/10.21608/resoncol.2022.114548.1159

    Article  Google Scholar 

  17. Yin Y, Liu W, Dai Y (2015) SOCS3 and its role in associated diseases. Hum Immunol 76:775–780

    Article  CAS  Google Scholar 

  18. Bao L, Fu X, Si M et al (2015) MicroRNA-185 targets SOCS3 to inhibit beta-cell dysfunction in diabetes. PLoS ONE 10:e0116067

    Article  Google Scholar 

  19. Madonna S, Scarponi C, Pallotta S et al (2012) Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis. Cell Death Dis 3:e334

    Article  CAS  Google Scholar 

  20. Sukka-Ganesh B, Larkin J 3rd (2016) Therapeutic potential for targeting the suppressor of cytokine signalling-1 pathway for the treatment of SLE. Scand J Immunol 84:299–309

    Article  CAS  Google Scholar 

  21. Carow B, Rottenberg ME (2014) SOCS3, a major regulator of infection and inflammation. Front Immunol 5:58

    Article  Google Scholar 

  22. Gao Y, Zhao H, Wang P et al (2018) The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scand J Immunol 88:e12727

    Article  Google Scholar 

  23. Raychaudhuri SP, Deodhar A (2014) The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun 48:128–133

    Article  Google Scholar 

  24. Mashima R (2015) Physiological roles of miR-155. Immunology 145:323–333

    Article  CAS  Google Scholar 

  25. Sheedy FJ (2015) Turning 21: induction of miR-21 as a key switch in the inflammatory response. Front Immunol 6:19

    Article  Google Scholar 

  26. Tao Y, Ai R, Hao Y et al (2019) Role of miR-155 in immune regulation and its relevance in oral lichen planus. Exp Ther Med 17:575–586

    CAS  Google Scholar 

  27. Scalavino V, Liso M, Serino G (2020) Role of microRNAs in the regulation of dendritic cell generation and function. Int J Mol Sci. https://doi.org/10.3390/ijms21041319

    Article  Google Scholar 

  28. Alivernini S, Gremese E, McSharry C et al (2017) MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis. Front Immunol 8:1932

    Article  Google Scholar 

  29. Hu R, Kagele DA, Huffaker TB et al (2014) miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41:605–619

    Article  CAS  Google Scholar 

  30. Escobar TM, Kanellopoulou C, Kugler DG et al (2014) miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40:865–879

    Article  CAS  Google Scholar 

  31. Yao R, Ma YL, Liang W et al (2012) MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7:e46082

    Article  CAS  Google Scholar 

  32. Murugaiyan G, Beynon V, Mittal A et al (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187:2213–2221

    Article  CAS  Google Scholar 

  33. Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-{beta}. J Biol Chem 285:41328–41336

    Article  CAS  Google Scholar 

  34. Maciak K, Dziedzic A, Miller E et al (2021) miR-155 as an important regulator of multiple sclerosis pathogenesis. a review. Int J Mol Sci. https://doi.org/10.3390/ijms22094332

    Article  Google Scholar 

  35. Ye YL, Pang Z, Gu W et al (2017) Expression of microRNA-155 in inflammatory bowel disease and its clinical significance. Zhonghua Yi Xue Za Zhi 97:3716–3719

    CAS  Google Scholar 

  36. Shumnalieva R, Kachakova D, Shoumnalieva-Ivanova V et al (2018) Whole peripheral blood miR-146a and miR-155 expression levels in systemic lupus erythematosus patients. Acta Reumatol Port 43:217–225

    Google Scholar 

  37. El-Komy M, Amin I, El-Hawary MS et al (2020) Upregulation of the miRNA-155, miRNA-210, and miRNA-20b in psoriasis patients and their relation to IL-17. Int J Immunopathol Pharmacol 34:2058738420933742

    Article  CAS  Google Scholar 

  38. Yoshimura A, Suzuki M, Sakaguchi R et al (2012) SOCS, inflammation, and autoimmunity. Front Immunol 3:20

    Article  Google Scholar 

  39. Liang Y, Xu WD, Peng H et al (2014) SOCS signaling in autoimmune diseases: molecular mechanisms and therapeutic implications. Eur J Immunol 44:1265–1275

    Article  CAS  Google Scholar 

  40. Lamana A, Villares R, Seoane IV et al (2020) Identification of a human SOCS1 polymorphism that predicts rheumatoid arthritis severity. Front Immunol 11:1336

    Article  CAS  Google Scholar 

  41. Toghi M, Taheri M, Arsang-Jang S et al (2017) SOCS gene family expression profile in the blood of multiple sclerosis patients. J Neurol Sci 375:481–485

    Article  CAS  Google Scholar 

  42. Zhai A, Qian J, Kao W et al (2013) Borna disease virus encoded phosphoprotein inhibits host innate immunity by regulating miR-155. Antiviral Res 98:66–75

    Article  CAS  Google Scholar 

  43. Salazar C, Galaz M, Ojeda N et al (2021) Expression of ssa-miR-155 during ISAV infection in vitro: putative role as a modulator of the immune response in salmo salar. Dev Comp Immunol 122:104109

    Article  CAS  Google Scholar 

  44. Liu S, Yan R, Chen B et al (2019) Influenza virus-induced robust expression of SOCS3 contributes to excessive production of IL-6. Front Immunol 10:1843

    Article  CAS  Google Scholar 

  45. Kwak JS, Kim KH (2021) Effect of miR-155 on type I interferon response in epithelioma papulosum cyprini cells. Fish Shellfish Immunol 111:1–5

    Article  CAS  Google Scholar 

  46. Todaro F, Tamassia N, Pinelli M et al (2019) Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression. Haematologica 104:e322–e325

    Article  Google Scholar 

  47. Gharibi T, Babaloo Z, Hosseini A et al (2020) Targeting STAT3 in cancer and autoimmune diseases. Eur J Pharmacol 878:173107

    Article  CAS  Google Scholar 

  48. Esmaeil Amini M, Shomali N, Bakhshi A et al (2020) Gut microbiome and multiple sclerosis: new insights and perspective. Int Immunopharmacol 88:107024

    Article  CAS  Google Scholar 

  49. Cevey ÁC, Penas FN, Alba Soto CD et al (2019) IL-10/STAT3/SOCS3 axis is involved in the anti-inflammatory effect of benznidazole. Front Immunol 10:1267

    Article  CAS  Google Scholar 

  50. Gharibi T, Majidi J, Kazemi T et al (2016) Biological effects of IL-21 on different immune cells and its role in autoimmune diseases. Immunobiology 221:357–367

    Article  CAS  Google Scholar 

  51. Dinesh P, Rasool M (2018) Multifaceted role of IL-21 in rheumatoid arthritis: current understanding and future perspectives. J Cell Physiol 233:3918–3928

    Article  CAS  Google Scholar 

  52. Deng XM, Yan SX, Wei W (2015) IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation. Cell Mol Immunol 12:31–39

    Article  CAS  Google Scholar 

  53. Holm TL, Tornehave D, Søndergaard H et al (2018) Evaluating IL-21 as a potential therapeutic target in crohn’s disease. Gastroenterol Res Pract 2018:5962624

    Article  Google Scholar 

  54. Ferreira RC, Simons HZ, Thompson WS et al (2015) IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia 58:781–790

    Article  CAS  Google Scholar 

  55. Ghalamfarsa G, Mahmoudi M, Mohammadnia-Afrouzi M et al (2016) IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis. J Immunotoxicol 13:274–285

    Article  CAS  Google Scholar 

  56. He Z, Jin L, Liu ZF et al (2012) Elevated serum levels of interleukin 21 are associated with disease severity in patients with psoriasis. Br J Dermatol 167:191–193

    Article  CAS  Google Scholar 

  57. Shi Y, Chen Z, Zhao Z et al (2019) IL-21 induces an imbalance of Th17/Treg cells in moderate-to-severe plaque psoriasis patients. Front Immunol 10:1865

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge Mr Sina Rahimpour and Dr Samira Vedadi for their assistance during the study.

Funding

This work was supported financially by the Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Grant No: 65139).

Author information

Authors and Affiliations

  1. Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mohammadsaleh Jahangir

  2. Department of Surgery, Alborz University of Medical Sciences, Karaj, Iran

    Mohammad Saeed Kahrizi

  3. Department of Urology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Natami

  4. Department of Oral and Maxillofacial Surgery, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Raziyeh Moaref Pour

  5. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Shadi Ghoreishizadeh, Navid Shomali & Siamak Sandoghchian Shotorbani

  6. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Maryam Hemmatzadeh, Navid Shomali & Siamak Sandoghchian Shotorbani

  7. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

    Hamed Mohammadi

  8. Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

    Hamed Mohammadi

  9. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Navid Shomali

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  1. Mohammadsaleh Jahangir
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Contributions

MJ, MSK, MN, RMP: investigation, methodology, writing—review and editing. SG, MH: methodology, investigation. HM: conceptualization, formal analysis. NS, SSS: conceptualization, writing-original draft, investigation, methodology, supervision.

Corresponding authors

Correspondence to Navid Shomali or Siamak Sandoghchian Shotorbani.

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This study was approved by the Ethical Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.294).

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Jahangir, M., Kahrizi, M.S., Natami, M. et al. MicroRNA-155 acts as a potential prognostic and diagnostic factor in patients with ankylosing spondylitis by modulating SOCS3. Mol Biol Rep 50, 553–563 (2023). https://doi.org/10.1007/s11033-022-08033-5

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