MicroRNA-211-5p Overexpression Effect on Endoplasmic Reticulum Stress and Apoptotic Genes in Fibroblast-like Synoviocytes of Rheumatoid Arthritis
-
Maryam Farghadan
,
Ahmad Zavaran-Hosseini
,
Elham Farhadi
,
Arash Sharafat Vaziri
,
Mohammad Naghi Tahmasebi
,
Ahmadreza Jamshidi
,
Mahdi Mahmoudi
Abstract
Fibroblast-like synoviocytes (FLSs) play a major role in the pathogenesis of rheumatoid arthritis (RA). Endoplasmic reticulum (ER) stress and dysregulation of unfolded protein response are involved in the resistance to apoptosis of FLSs in RA (RA-FLSs). MicroRNA (MiR)-211 plays an important role in controlling ER stress and apoptotic genes in a PKR-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-dependent manner. We investigated the effect of miR-211-5p overexpression on ER stress and apoptotic genes in RA-FLSs.
FLSs were isolated from synovial tissues of trauma (n=10) and RA (n=10) patients. MiR-211-5p and mRNA expression of the selected genes involved in the PERK pathway and apoptosis regulation were measured in RA, trauma, and thapsigargin (Tg)-treated RA-FLSs. Afterward, Tg-treated RA-FLSs following miR-211-5p overexpression were evaluated for miR-211-5p and mRNA levels of the study genes.
The expression of miR-211-5p, PERK, BAX, and BCL2 showed no differences between RA and trauma. However, the expression of ATF4 and BCL-XL showed a significant increase in trauma. In addition, the levels of C/EBP homologous protein (CHOP) and MCL1 indicated a significant increase in RA-FLSs. Tg treatment significantly increased the expression of PERK, ATF4, and CHOP in RA-FLSs with no effect on miR-211-5p, BAX, BCL2, BCL-XL, and MCL1. Furthermore, Tg treatment following miR-211-5p overexpression in RA-FLSs showed a significant increase in levels of miR-211-5p with no changes in apoptotic genes.
MiR-211-5p overexpression in stimulated RA-FLSs did not alter the levels of selected genes involved in apoptosis regulation. However, more investigations are necessary to determine the ER stress role in apoptosis regulation in RA-FLSs.
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3. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46(2):183-96.
4. Šenolt L, Grassi W, Szodoray P. Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis? BMC medicine. 2014;12(1):49.
5. Alam J, Jantan I, Bukhari SNA. Rheumatoid arthritis: recent advances on its etiology, role of cytokines and pharmacotherapy. Biomedicine & Pharmacotherapy. 2017;92:615-33.
6. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nature Reviews Disease Primers. 2018;4:18001.
7. Tanaka Y. Rheumatoid arthritis. Inflammation and regeneration. 2020;40:20. PubMed PMID: 32944095. Pubmed Central PMCID: PMC7487964. Epub 2020/09/19. eng.
8. Korb A, Pavenstädt H, Pap T. Cell death in rheumatoid arthritis. Apoptosis. 2009;14(4):447-54.
9. Bartok B, Firestein GS. Fibroblast‐like synoviocytes: key effector cells in rheumatoid arthritis. Immunological reviews. 2010;233(1):233-55.
10. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology. 2013;9(1):24.
11. Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. Journal of immunology research. 2016;2016.
12. Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis research & therapy. 2017;19(1):110.
13. Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nature Reviews Rheumatology. 2020;16(6):316-33.
14. Morito D, Nagata K. ER stress proteins in autoimmune and inflammatory diseases. Frontiers in immunology. 2012;3:48.
15. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nature reviews Molecular cell biology. 2020;21(8):421-38.
16. Karagöz GE, Aragón T, Acosta-Alvear D. Recent advances in signal integration mechanisms in the unfolded protein response. F1000Research. 2019;8.
17. Liu Z, Lv Y, Zhao N, Guan G, Wang J. Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell death & disease. 2015;6(7):e1822-e.
18. Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Current molecular medicine. 2016;16(6):533-44.
19. Hiramatsu N, Chiang W-C, Kurt TD, Sigurdson CJ, Lin JH. Multiple mechanisms of unfolded protein response–induced cell death. The American journal of pathology. 2015;185(7):1800-8.
20. Li Y, Guo Y, Tang J, Jiang J, Chen Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta biochimica et biophysica Sinica. 2014;46(8):629-40.
21. Rahmati M, Moosavi MA, McDermott MF. ER Stress: A Therapeutic Target in Rheumatoid Arthritis? Trends in pharmacological sciences. 2018.
22. Junjappa RP, Patil P, Bhattarai KR, Kim H-R, Chae H-J. IRE1α implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases. Frontiers in immunology. 2018;9.
23. Park Y-J, Yoo S-A, Kim W-U. Role of endoplasmic reticulum stress in rheumatoid arthritis pathogenesis. Journal of Korean medical science. 2014;29(1):2-11.
24. Todd DJ, Lee A-H, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Reviews Immunology. 2008;8(9):663.
25. Liu Q, Körner H, Wu H, Wei W. Endoplasmic reticulum stress in autoimmune diseases. Immunobiology. 2020;225(2):151881.
26. Jang JH, Lee T-J. The role of microRNAs in cell death pathways. Yeungnam University Journal of Medicine. 2021;38(2):107.
27. McMahon M, Samali A, Chevet E. Regulation of the unfolded protein response by noncoding RNA. American Journal of Physiology-Cell Physiology. 2017;313(3):C243-C54.
28. Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, et al. miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Molecular cell. 2012;48(3):353-64.
29. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism. 2010;62(9):2569-81.
30. Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods in enzymology. 490: Elsevier; 2011. p. 71-92.
31. Yoo S-A, You S, Yoon H-J, Kim D-H, Kim H-S, Lee K, et al. A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis. Journal of Experimental Medicine. 2012;209(4):871-86.
32. Connor AM, Mahomed N, Gandhi R, Keystone EC, Berger SA. TNFα modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts. Arthritis research & therapy. 2012;14(2):1-19.
33. Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38(12):1336-45.
34. Gotoh T, Endo M, Oike Y. Endoplasmic reticulum stress-related inflammation and cardiovascular diseases. International Journal of Inflammation. 2011;2011.
35. Wortel IM, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism. 2017;28(11):794-806.
36. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell death and differentiation. 2004;11(4):381.
37. Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clinical Science. 2010;118(1):19-29.
38. Jäger R, Bertrand MJ, Gorman AM, Vandenabeele P, Samali A. The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. Biology of the Cell. 2012;104(5):259-70.
39. Lin JH, Walter P, Yen TB. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol Mech Dis. 2008;3:399-425.
40. Hu H, Tian M, Ding C, Yu S. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Frontiers in immunology. 2019:3083.
41. Liu H, Eksarko P, Temkin V, Haines GK, Perlman H, Koch AE, et al. Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis. The Journal of Immunology. 2005;175(12):8337-45.
42. Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, debock CE, Thorne RF, et al. Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Research. 2008;68(16):6708-17.
43. Kabala PA, Angiolilli C, Yeremenko N, Grabiec AM, Giovannone B, Pots D, et al. Endoplasmic reticulum stress cooperates with Toll-like receptor ligation in driving activation of rheumatoid arthritis fibroblast-like synoviocytes. Arthritis research & therapy. 2017;19(1):1-11.
44. Díaz-Martínez M, Benito-Jardón L, Alonso L, Koetz-Ploch L, Hernando E, Teixidó J. miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma. Cancer research. 2018;78(4):1017-30.
45. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. Journal of Biological Chemistry. 2010;285(9):6091-100.
46. Vandewynckel Y-P, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatology international. 2015;9(1):93-104.
47. Ge X, Frank-Bertoncelj M, Klein K, McGovern A, Kuret T, Houtman M, et al. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability. Genome biology. 2021;22(1):1-39.
48. Bu Y, Yoshida A, Chitnis N, Altman BJ, Tameire F, Oran A, et al. A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nature cell biology. 2018;20(1):104.
49. Han J, Back SH, Hur J, Lin Y-H, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nature cell biology. 2013;15(5):481-90.
50. Wang J, Yan S, Yang J, Lu H, Xu D, Wang Z. Non-coding RNAs in rheumatoid arthritis: from bench to bedside. Frontiers in immunology. 2020:3129.
2. Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. Jama. 2018;320(13):1360-72.
3. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46(2):183-96.
4. Šenolt L, Grassi W, Szodoray P. Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis? BMC medicine. 2014;12(1):49.
5. Alam J, Jantan I, Bukhari SNA. Rheumatoid arthritis: recent advances on its etiology, role of cytokines and pharmacotherapy. Biomedicine & Pharmacotherapy. 2017;92:615-33.
6. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nature Reviews Disease Primers. 2018;4:18001.
7. Tanaka Y. Rheumatoid arthritis. Inflammation and regeneration. 2020;40:20. PubMed PMID: 32944095. Pubmed Central PMCID: PMC7487964. Epub 2020/09/19. eng.
8. Korb A, Pavenstädt H, Pap T. Cell death in rheumatoid arthritis. Apoptosis. 2009;14(4):447-54.
9. Bartok B, Firestein GS. Fibroblast‐like synoviocytes: key effector cells in rheumatoid arthritis. Immunological reviews. 2010;233(1):233-55.
10. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology. 2013;9(1):24.
11. Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. Journal of immunology research. 2016;2016.
12. Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis research & therapy. 2017;19(1):110.
13. Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nature Reviews Rheumatology. 2020;16(6):316-33.
14. Morito D, Nagata K. ER stress proteins in autoimmune and inflammatory diseases. Frontiers in immunology. 2012;3:48.
15. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nature reviews Molecular cell biology. 2020;21(8):421-38.
16. Karagöz GE, Aragón T, Acosta-Alvear D. Recent advances in signal integration mechanisms in the unfolded protein response. F1000Research. 2019;8.
17. Liu Z, Lv Y, Zhao N, Guan G, Wang J. Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell death & disease. 2015;6(7):e1822-e.
18. Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Current molecular medicine. 2016;16(6):533-44.
19. Hiramatsu N, Chiang W-C, Kurt TD, Sigurdson CJ, Lin JH. Multiple mechanisms of unfolded protein response–induced cell death. The American journal of pathology. 2015;185(7):1800-8.
20. Li Y, Guo Y, Tang J, Jiang J, Chen Z. New insights into the roles of CHOP-induced apoptosis in ER stress. Acta biochimica et biophysica Sinica. 2014;46(8):629-40.
21. Rahmati M, Moosavi MA, McDermott MF. ER Stress: A Therapeutic Target in Rheumatoid Arthritis? Trends in pharmacological sciences. 2018.
22. Junjappa RP, Patil P, Bhattarai KR, Kim H-R, Chae H-J. IRE1α implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases. Frontiers in immunology. 2018;9.
23. Park Y-J, Yoo S-A, Kim W-U. Role of endoplasmic reticulum stress in rheumatoid arthritis pathogenesis. Journal of Korean medical science. 2014;29(1):2-11.
24. Todd DJ, Lee A-H, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Reviews Immunology. 2008;8(9):663.
25. Liu Q, Körner H, Wu H, Wei W. Endoplasmic reticulum stress in autoimmune diseases. Immunobiology. 2020;225(2):151881.
26. Jang JH, Lee T-J. The role of microRNAs in cell death pathways. Yeungnam University Journal of Medicine. 2021;38(2):107.
27. McMahon M, Samali A, Chevet E. Regulation of the unfolded protein response by noncoding RNA. American Journal of Physiology-Cell Physiology. 2017;313(3):C243-C54.
28. Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, et al. miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Molecular cell. 2012;48(3):353-64.
29. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism. 2010;62(9):2569-81.
30. Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods in enzymology. 490: Elsevier; 2011. p. 71-92.
31. Yoo S-A, You S, Yoon H-J, Kim D-H, Kim H-S, Lee K, et al. A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis. Journal of Experimental Medicine. 2012;209(4):871-86.
32. Connor AM, Mahomed N, Gandhi R, Keystone EC, Berger SA. TNFα modulates protein degradation pathways in rheumatoid arthritis synovial fibroblasts. Arthritis research & therapy. 2012;14(2):1-19.
33. Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38(12):1336-45.
34. Gotoh T, Endo M, Oike Y. Endoplasmic reticulum stress-related inflammation and cardiovascular diseases. International Journal of Inflammation. 2011;2011.
35. Wortel IM, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism. 2017;28(11):794-806.
36. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell death and differentiation. 2004;11(4):381.
37. Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clinical Science. 2010;118(1):19-29.
38. Jäger R, Bertrand MJ, Gorman AM, Vandenabeele P, Samali A. The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. Biology of the Cell. 2012;104(5):259-70.
39. Lin JH, Walter P, Yen TB. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol Mech Dis. 2008;3:399-425.
40. Hu H, Tian M, Ding C, Yu S. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Frontiers in immunology. 2019:3083.
41. Liu H, Eksarko P, Temkin V, Haines GK, Perlman H, Koch AE, et al. Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis. The Journal of Immunology. 2005;175(12):8337-45.
42. Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, debock CE, Thorne RF, et al. Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Research. 2008;68(16):6708-17.
43. Kabala PA, Angiolilli C, Yeremenko N, Grabiec AM, Giovannone B, Pots D, et al. Endoplasmic reticulum stress cooperates with Toll-like receptor ligation in driving activation of rheumatoid arthritis fibroblast-like synoviocytes. Arthritis research & therapy. 2017;19(1):1-11.
44. Díaz-Martínez M, Benito-Jardón L, Alonso L, Koetz-Ploch L, Hernando E, Teixidó J. miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma. Cancer research. 2018;78(4):1017-30.
45. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. Journal of Biological Chemistry. 2010;285(9):6091-100.
46. Vandewynckel Y-P, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatology international. 2015;9(1):93-104.
47. Ge X, Frank-Bertoncelj M, Klein K, McGovern A, Kuret T, Houtman M, et al. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability. Genome biology. 2021;22(1):1-39.
48. Bu Y, Yoshida A, Chitnis N, Altman BJ, Tameire F, Oran A, et al. A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nature cell biology. 2018;20(1):104.
49. Han J, Back SH, Hur J, Lin Y-H, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nature cell biology. 2013;15(5):481-90.
50. Wang J, Yan S, Yang J, Lu H, Xu D, Wang Z. Non-coding RNAs in rheumatoid arthritis: from bench to bedside. Frontiers in immunology. 2020:3129.
| Files | ||
| Issue | Vol 21 No 4 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i4.10289 | |
| Keywords | ||
| Endoplasmic reticulum stress Fibroblast-like synoviocytes MiR-211-5p Rheumatoid arthritis | ||
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How to Cite
1.
Farghadan M, Zavaran-Hosseini A, Farhadi E, Sharafat Vaziri A, Tahmasebi MN, Jamshidi A, Mahmoudi M. MicroRNA-211-5p Overexpression Effect on Endoplasmic Reticulum Stress and Apoptotic Genes in Fibroblast-like Synoviocytes of Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2022;21(4):418-428.
