Serum Exosomal Expression of miR-155 and miR-221 in Moderate-to-severe Asthmatic Patients
-
Zeynab Rostamzadeh Khoie
,
Neda K. Dezfuli
,
Mohammad Varahram
,
Atefeh Fakharian
,
Seyed Alireza Mahdaviani
,
Hamidreza Jamaati
,
Ian M. Adcock
,
Esmaeil Mortaz
Abstract
The cardinal features of asthma include airway inflammation, airway hyper responsiveness (AHR) and airway remodeling. Exosomes help orchestrate the immune response and contain microRNAs (miRNAs) such as miRNA-155 and miRNA-221 which play significant roles in the pathogenesis and exacerbations of severe asthma. In this study, we aimed to investigate the exosomal expression of miRNAs (155, 221) in the serum of severe asthma patients.
Eighteen moderate-to-severe asthma patients and eighteen healthy subjects were recruited for this study. Serum exosomes were isolated and characterized according to their shape, size, and exosomal markers by transmission electron microscopy, dynamic light scattering (DLS) and flow cytometry, respectively. Exosomal miRNA extraction and quantitative real-time PCR (qRT-PCR) were used to measure miR-155 and miR-221. Besides the forced expiratory volume in 1 second and forced vital capacity (FVC) were evaluated in the patient groups.
Round exosomes with a mean size of 25.8 nm were isolated from serum of asthmatic patients. Flow cytometry shows high expression of CD63 and CD81 on isolated exosomes. Serum exosomes from severe asthma patients and healthy donors contained miR-155 and miR-221 but miR-155 and miR-221 expression levels were significantly increased in severe asthma patients. There was a positive correlation between miR-221 expression and FVC).
Receiver operating characteristic (ROC) analysis indicated that miR-155 and miR-221 had an excellent diagnostic efficiency in predicting asthma (AUC=0.91 and AUC=0.76, respectively). Serum exosomal miR-155 and miR-221 may be a potential biomarker for severe asthma. However, the results need to be validated in another cohort, and further studies with larger samples size should be conducted on the effects of these miRNAs on effector cells.
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14. Malmhäll C, Alawieh S, Lu Y, Sjöstrand M, Bossios A, Eldh M, et al. MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung. Journal of Allergy and Clinical Immunology. 2014;133(5):1429-1438.e7.
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19. Liu G, Abraham E. MicroRNAs in Immune Response and Macrophage Polarization. ATVB. 2013;33(2):170–7.
20. Alipoor SD, Adcock IM, Garssen J, Mortaz E, Varahram M, Mirsaeidi M, et al. The roles of miRNAs as potential biomarkers in lung diseases. Europ J Pharmacol. 2016;791(19):395–404.
21. Alipoor S ME, Tabarsi P, Marjani M, Varahram M, Folkerts G, Garssen J, Adcock I. miR-1224 Expression Is Increased in Human Macrophages after Infection with Bacillus Calmette-Guérin (BCG).
22. Sastre B, Cañas JA, Rodrigo-Muñoz JM, Del Pozo V. Novel Modulators of Asthma and Allergy: Exosomes and MicroRNAs. Front Immunol. 2017;8(2):826.
23. Alipoor SD, Mortaz E, Garssen J, Movassaghi M, Mirsaeidi M, Adcock IM. Exosomes and Exosomal miRNA in Respiratory Diseases. Med Inflamm. 2016;2016(15):1–11.
24. Zhao L, Yu J, Wang J, Li H, Che J, Cao B. Isolation and Identification of miRNAs in exosomes derived from serum of colon cancer patients. J Cancer. 2017;8(7):1145–52.
25. Rajagopal C, Harikumar KB. The Origin and Functions of Exosomes in Cancer. Front Oncol. 2018;8:66.
26. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):1208–15.
27. Sato-Kuwabara Y, Melo SA, Soares FA, Calin GA. The fusion of two worlds: Non-coding RNAs and extracellular vesicles - diagnostic and therapeutic implications (Review). Int J Oncol. 2015;46(1):17–27.
28. Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, et al. Recent advancements in the use of exosomes as drug delivery systems. J Nanobiotechnol. 2018;16(1):81.
29. Mortaz E, Alipoor SD, Varahram M, Jamaati H, Garssen J, Mumby SE, et al. Exosomes in Severe Asthma: Update in Their Roles and Potential in Therapy. Bio Med Res Int. 2018;2018:1–10.
30. Tzimagiorgis G, Michailidou EZ, Kritis A, Markopoulos AK, Kouidou S. Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiology. 2011;35(6):580–9.
31. Michael A, Bajracharya S, Yuen P, Zhou H, Star R, Illei G, et al. Exosomes from human saliva as a source of microRNA biomarkers: microRNA biomarkers in salivary exosomes. Oral Dis. 2010;16(1):34–8.
32. Manterola L, Guruceaga E, Pérez-Larraya JG, González-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol. 2014;16(4):520–7.
33. Zhang H, Song Y, Rong W, Fan L, Cai Y, Qu Q, et al. miR-221 participates in the airway epithelial cells injury in asthma via targeting SIRT1. Experimental Lung Research. 2018;44(6):272–9.
34. Alashkar Alhamwe B, Potaczek DP, Miethe S, Alhamdan F, Hintz L, Magomedov A, et al. Extracellular Vesicles and Asthma—More Than Just a Co-Existence. IJMS. 2021;22(9):4984.
35. Alipoor SD, Mortaz E, Tabarsi P, Farnia P, Mirsaeidi M, Garssen J, et al. Bovis Bacillus Calmette–Guerin (BCG) infection induces exosomal miRNA release by human macrophages. J Transl Med. 2017;15(1):105.
36. Moloudizargari M, Redegeld F, Asghari MH, Mosaffa N, Mortaz E. Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity. DARU J Pharm Sci. 2020;28(2):647–59.
37. Gonzalez-Villasana V, Rashed MH, Gonzalez-Cantú Y, Bayraktar R, Menchaca-Arredondo JL, Vazquez-Guillen JM, et al. Presence of Circulating miR-145, miR-155, and miR-382 in Exosomes Isolated from Serum of Breast Cancer Patients and Healthy Donors. Dis Markers. 2019;2019:1–9.
38. Perry MM, Adcock IM, Chung KF. Role of microRNAs in allergic asthma: present and future. Curr Opin Allergy Clin Immunol. 2015;15(2):156–62.
39. Lommatzsch M, Virchow JC. Severe asthma: definition, diagnosis and treatment. Dtsch Arztebl Int. 2014 Dec 12;111(50):847-55.
40. Tubita V, Callejas‐Díaz B, Roca‐Ferrer J, Marin C, Liu Z, Wang DY, et al. Role of microRNAs in inflammatory upper airway diseases. Allergy. 2021;76(7):1967–80.
41. Lu TX, Sherrill JD, Wen T, Plassard AJ, Besse JA, Abonia JP, et al. MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol. 2012;129(4):1064-1075.e9.
2. Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients. Journal of Allergy and Clinical Immunology. 2018;141(1):110-116.e7.
3. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.
4. Boateng E, Kovacevic D, Oldenburg V, Rådinger M, Krauss-Etschmann S. Role of airway epithelial cell miRNAs in asthma. Front Allergy. 2022;3(1):962693.
5. 5. PR Pinkerton MH, Maru SY, Jefferson SJ, Roff AN, Ishmael FT. Differential microRNA epression in asthma and the role of miR-1248 in regulation of IL-5. Am J Clin Exp Immunol. 2012;1(2):154-65.
6. Perry MM, Baker JE, Gibeon DS, Adcock IM, Chung KF. Airway Smooth Muscle Hyperproliferation Is Regulated by MicroRNA-221 in Severe Asthma. Am J Respir Cell Mol Biol. 2014;50(1):7–17.
7. Lu TX, Rothenberg ME. MicroRNA. Journal of Allergy and Clinical Immunology. 2018;141(4):1202–7.
8. Lu M, DiBernardo E, Parks E, Fox H, Zheng SY, Wayne E. The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Autoimmune Disorders. Front Immunol. 2021. 24;12:566299.
9. Kok VC, Yu CC. Cancer-Derived Exosomes: Their Role in Cancer Biology and Biomarker Development. Int J Nanomedicine. 2020;15:8019–36.
10. Kai W, Qian XU, Qun WUZ. MicroRNAs and Asthma Regulation. Iran J Allergy Asthma Immunol. 2015r;14(2):120–5.
11. Yang N, Cheng H, Mo Q, Zhou X, Xie M. miR 155 5p downregulation inhibits epithelial to mesenchymal transition by targeting SIRT1 in human nasal epithelial cells. Mol Med Rep. 2020 Nov;22(5):3695-3704.
12. Pan J, Yang Q, Zhou Y, Deng H, Zhu Y, Zhao D, et al. MicroRNA-221 Modulates Airway Remodeling via the PI3K/AKT Pathway in OVA-Induced Chronic Murine Asthma. Front Cell Dev Biol. 2020;8(5):495.
13. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for Normal Immune Function. Science. 2007;316(5824):608–11.
14. Malmhäll C, Alawieh S, Lu Y, Sjöstrand M, Bossios A, Eldh M, et al. MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung. Journal of Allergy and Clinical Immunology. 2014;133(5):1429-1438.e7.
15. Wang J, Zhang KY, Liu SM, Sen S. Tumor-Associated Circulating MicroRNAs as Biomarkers of Cancer. Molecules. 2014;19(2):1912–38.
16. Atashbasteh M, Mortaz E, Mahdaviani SA, Jamaati H, Allameh A. Expression levels of plasma exosomal miR-124, miR-125b, miR-133b, miR-130a and miR-125b-1-3p in severe asthma patients and normal individuals with emphasis on inflammatory factors. Allergy Asthma Clin Immunol. 2021;17(1):51.
17. Dezfuli NK, Adcock IM, Alipoor SD, Seyfi S, Salimi B, Mafi Golchin M, et al. The miR-146a SNP Rs2910164 and miR-155 SNP rs767649 Are Risk Factors for Non-Small Cell Lung Cancer in the Iranian Population. Tremblay Y, editor. Canadian Resp J. 2020;20:1–8.
18. Dezfuli NK, Alipoor SD, Dalil Roofchayee N, Seyfi S, Salimi B, Adcock IM, et al. Evaluation Expression of miR-146a and miR-155 in Non-Small-Cell Lung Cancer Patients. Front Oncol. 2021;11(5):715677.
19. Liu G, Abraham E. MicroRNAs in Immune Response and Macrophage Polarization. ATVB. 2013;33(2):170–7.
20. Alipoor SD, Adcock IM, Garssen J, Mortaz E, Varahram M, Mirsaeidi M, et al. The roles of miRNAs as potential biomarkers in lung diseases. Europ J Pharmacol. 2016;791(19):395–404.
21. Alipoor S ME, Tabarsi P, Marjani M, Varahram M, Folkerts G, Garssen J, Adcock I. miR-1224 Expression Is Increased in Human Macrophages after Infection with Bacillus Calmette-Guérin (BCG).
22. Sastre B, Cañas JA, Rodrigo-Muñoz JM, Del Pozo V. Novel Modulators of Asthma and Allergy: Exosomes and MicroRNAs. Front Immunol. 2017;8(2):826.
23. Alipoor SD, Mortaz E, Garssen J, Movassaghi M, Mirsaeidi M, Adcock IM. Exosomes and Exosomal miRNA in Respiratory Diseases. Med Inflamm. 2016;2016(15):1–11.
24. Zhao L, Yu J, Wang J, Li H, Che J, Cao B. Isolation and Identification of miRNAs in exosomes derived from serum of colon cancer patients. J Cancer. 2017;8(7):1145–52.
25. Rajagopal C, Harikumar KB. The Origin and Functions of Exosomes in Cancer. Front Oncol. 2018;8:66.
26. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):1208–15.
27. Sato-Kuwabara Y, Melo SA, Soares FA, Calin GA. The fusion of two worlds: Non-coding RNAs and extracellular vesicles - diagnostic and therapeutic implications (Review). Int J Oncol. 2015;46(1):17–27.
28. Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, et al. Recent advancements in the use of exosomes as drug delivery systems. J Nanobiotechnol. 2018;16(1):81.
29. Mortaz E, Alipoor SD, Varahram M, Jamaati H, Garssen J, Mumby SE, et al. Exosomes in Severe Asthma: Update in Their Roles and Potential in Therapy. Bio Med Res Int. 2018;2018:1–10.
30. Tzimagiorgis G, Michailidou EZ, Kritis A, Markopoulos AK, Kouidou S. Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiology. 2011;35(6):580–9.
31. Michael A, Bajracharya S, Yuen P, Zhou H, Star R, Illei G, et al. Exosomes from human saliva as a source of microRNA biomarkers: microRNA biomarkers in salivary exosomes. Oral Dis. 2010;16(1):34–8.
32. Manterola L, Guruceaga E, Pérez-Larraya JG, González-Huarriz M, Jauregui P, Tejada S, et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol. 2014;16(4):520–7.
33. Zhang H, Song Y, Rong W, Fan L, Cai Y, Qu Q, et al. miR-221 participates in the airway epithelial cells injury in asthma via targeting SIRT1. Experimental Lung Research. 2018;44(6):272–9.
34. Alashkar Alhamwe B, Potaczek DP, Miethe S, Alhamdan F, Hintz L, Magomedov A, et al. Extracellular Vesicles and Asthma—More Than Just a Co-Existence. IJMS. 2021;22(9):4984.
35. Alipoor SD, Mortaz E, Tabarsi P, Farnia P, Mirsaeidi M, Garssen J, et al. Bovis Bacillus Calmette–Guerin (BCG) infection induces exosomal miRNA release by human macrophages. J Transl Med. 2017;15(1):105.
36. Moloudizargari M, Redegeld F, Asghari MH, Mosaffa N, Mortaz E. Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity. DARU J Pharm Sci. 2020;28(2):647–59.
37. Gonzalez-Villasana V, Rashed MH, Gonzalez-Cantú Y, Bayraktar R, Menchaca-Arredondo JL, Vazquez-Guillen JM, et al. Presence of Circulating miR-145, miR-155, and miR-382 in Exosomes Isolated from Serum of Breast Cancer Patients and Healthy Donors. Dis Markers. 2019;2019:1–9.
38. Perry MM, Adcock IM, Chung KF. Role of microRNAs in allergic asthma: present and future. Curr Opin Allergy Clin Immunol. 2015;15(2):156–62.
39. Lommatzsch M, Virchow JC. Severe asthma: definition, diagnosis and treatment. Dtsch Arztebl Int. 2014 Dec 12;111(50):847-55.
40. Tubita V, Callejas‐Díaz B, Roca‐Ferrer J, Marin C, Liu Z, Wang DY, et al. Role of microRNAs in inflammatory upper airway diseases. Allergy. 2021;76(7):1967–80.
41. Lu TX, Sherrill JD, Wen T, Plassard AJ, Besse JA, Abonia JP, et al. MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol. 2012;129(4):1064-1075.e9.
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| Issue | Vol 24 No 2 (2025) | |
| Section | Original Article(s) | |
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| Exosome miRNA-155 miRNA-221 Serum Severe asthma | ||
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How to Cite
1.
Rostamzadeh Khoie Z, Dezfuli N, Varahram M, Fakharian A, Mahdaviani SA, Jamaati H, Adcock I, Mortaz E. Serum Exosomal Expression of miR-155 and miR-221 in Moderate-to-severe Asthmatic Patients. Iran J Allergy Asthma Immunol. 2025;24(2):153-163.
