Lncrna NEAT1 Regulates Th1/Th2 in Pediatric Asthma by Targeting Microrna-217/GATA3
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Abstract
Background: The imbalance of immune response between helper Th1 and Th2 cells is the direct cause of asthma. It was closely related to abnormal expression of lncRNAs. However, whether lncRNAs can regulate Th1/Th2 balance in pediatric asthma remains to be investigated.
Methods: Peripheral blood samples were collected from children with asthma and normal volunteers at the Children’s Hospital of Shaanxi Provincial People’s Hospital (Xi’an, China) in 2020. The qRT-PCR was used to detect the expression of lncRNA NEAT1, miR-217 and GATA3 in peripheral blood samples. The effects of lncRNA NEAT1, miR-217, and GATA3 on CD4+T cell population were detected in vitro. Meanwhile, the regulatory effect of lncRNA NEAT1/miR-217/GATA3 was evaluated through the dual luciferase report assay, functional assays and animal experiments.
Results: We investigated that lncRNA NEAT1 and GATA3 was significantly up-regulated in CD4+T cells in peripheral blood of children with asthma (P<0.001). Knockdown of lncRNA NEAT1 or GATA3 significantly reduced Th2-related cytokines (P<0.05), but had no effect on Th1 cells. Importantly, the interactions of lncRNA NEAT1 with miR-217 and miR-217 with GATA3 were confirmed by dual luciferase report assay. Meanwhile, functional assays and animal experiments demonstrated that lncRNA NEAT1 regulated GATA3 expression through sponge miR-217, thereby regulating Th1/Th2 balance in CD4+T cells in pediatric asthma.
Conclusion: lncRNA NEAT1/miR-217/GATA3 axis may reveal the immunological mechanism of pediatric asthma, which has potential clinical application value in the future.
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23. Qiu YY, Wu Y, Lin MJ, et al (2019). LncRNA-MEG3 functions as a competing endogenous RNA to regulate Treg/Th17 balance in patients with asthma by targeting microRNA-17/ RORgammat. Biomed Pharmacother, 111:386-394.
24. Li X, Ye S, Lu Y (2020). Long non-coding RNA NEAT1 overexpression associates with increased exacerbation risk, severity, and inflammation, as well as decreased lung function through the interaction with microRNA-124 in asthma. J Clin Lab Anal, 34:e23023.
25. Jiang Y, Zhao Y, Mo X (2021). Expression of lncRNA NEAT1 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and its correlation with Th1/Th2 balance. Int J Clin Exp Pathol, 14:646-652.
26. Zhou RS, Zhang EX, Sun QF, Ye ZJ, Liu JW, Zhou DH, Tang Y (2019). Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue. BMC Cancer, 19:779.
27. Duan XJ, Zhang X, Ding N, Zhang JY, Chen YP (2021). LncRNA NEAT1 regulates MMP-16 by targeting miR-200a/b to aggravate inflammation in asthma. Autoimmunity, 54:439-449.
28. Krug N, Hohlfeld JM, Kirsten AM, et al (2015). Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med, 372:1987-1995.
29. Gavitt TD, Hartmann AK, Sawant SS, Mara AB, Szczepanek SM, Rouge JL (2021). A GATA3 Targeting Nucleic Acid Nanocapsule for In Vivo Gene Regulation in Asthma. ACS Nano.
30. Ray A, Cohn L (1999). Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest, 104:985-993.
31. Yamashita N, Tashimo H, Ishida H, et al (2006). Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol, 290:L1045-1051.
32. Li W, Zhang Z, Liu X, Xiao C, Shang Y (2017). The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Invest, 127:3421-3440.
2. Masoli M, Fabian D, Holt S, Beasley R (2004). The global burden of asthma executive summary of the GINA Dissemination Committee report. Allergy, 59:469-478.
3. Ferkol T, Schraufnagel D (2014). The global burden of respiratory disease. Ann Am Thorac Soc, 11:404-406.
4. Zhu M, Liang Z, Wang T, Chen R, Wang G, Ji Y (2016). Th1/Th2/Th17 cells imbalance in patients with asthma with and without psychological symptoms. Allergy Asthma Proc, 37:148-156.
5. Rogala B, Bozek A, Gluck J, Jarzab J (2015). Prevalence of IgE-mediated allergy and evaluation of Th1/Th2 cytokine profiles in patients with severe bronchial asthma. Postepy Dermatol Alergol, 32:274-280.
6. Diao M, Min J, Guo F, Zhang CL (2017). Effects of salbutamol aerosol combined with magnesium sulfate on T-lymphocyte subgroup and Th1/Th2 cytokines of pediatric asthma. Exp Ther Med, 13:117-120.
7. Hao M, Zan J (2021). The Identification of Childhood Asthma Progression-Related lncRNAs and mRNAs Suitable as Biomarkers Using Weighted Gene Coexpression Network Analysis. Genet Res (Camb), 2021:5511507.
8. Liang WC, Fu WM, Wong CW, et al (2015). The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget, 6:22513-25.
9. Yin H, Liu MH, Gao F, Shang HM (2021). Pro-inflammatory and pro-fibrotic role of long non-coding RNA RMRP in pediatric asthma through targeting microRNA-206/CCL2 axis. J Biol Regul Homeost Agents, 35:71-83.
10. Foronjy R (2020). Commentary on: The potency of lncRNA MALAT1/miR-155 in altering asthmatic Th1/Th2 balance by modulation of CTLA4. Bioscience Reports, 40.
11. Zhang D, Cohn L, Ray P, Bottomly K, Ray A (1997). Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem, 272:21597-21603.
12. Ouyang W, Ranganath SH, Weindel K, et al (1998). Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity, 9:745-755.
13. Qiu YY, Zhang YW, Qian XF, Bian T (2017). miR-371, miR-138, miR-544, miR-145, and miR-214 could modulate Th1/Th2 balance in asthma through the combinatorial regulation of Runx3. Am J Transl Res, 9:3184-3199.
14. Kisuya J, Chemtai A, Raballah E, Keter A, Ouma C (2019). The diagnostic accuracy of Th1 (IFN-γ, TNF-α, and IL-2) and Th2 (IL-4, IL-6 and IL-10) cytokines response in AFB microscopy smear negative PTB- HIV co-infected patients. Sci Rep, 9:2966.
15. Britt RD, Jr., Thompson MA, Sasse S, Pabelick CM, Gerber AN, Prakash YS (2019). Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol, 316:L71-l81.
16. Espinosa Gonzalez M, Volk-Draper L, Bhattarai N, Wilber A, Ran S (2022). Th2 Cytokines IL-4, IL-13, and IL-10 Promote Differentiation of Pro-Lymphatic Progenitors Derived from Bone Marrow Myeloid Precursors. Stem Cells Dev, 31:322-333.
17. Tsuji Y (2020). Transmembrane protein western blotting: Impact of sample preparation on detection of SLC11A2 (DMT1) and SLC40A1 (ferroportin). PLoS One, 15:e0235563.
18. Liang P, Peng S, Zhang M, Ma Y, Zhen X, Li H (2017). Huai Qi Huang corrects the balance of Th1/Th2 and Treg/Th17 in an ovalbumin -induced asthma mouse model. Biosci Rep, 37:BSR20171071.
19. James CV, Rosenbaum S (2009). Paying for quality care: implications for racial and ethnic health disparities in pediatric asthma. Pediatrics, 123 Suppl 3:S205-210.
20. Muehling LM, Lawrence MG, Woodfolk JA (2017). Pathogenic CD4(+) T cells in patients with asthma. J Allergy Clin Immunol, 140:1523-1540.
21. Kannan AK, Sahu N, Mohanan S, Mohinta S, August A (2013). IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-gamma in naive CD4+ T cells. J Allergy Clin Immunol, 132:811-20 e1-5.
22. Qi X, Chen H, Huang Z, et al (2018). Aberrantly expressed lncRNAs identified by microarray analysis in CD4(+)T cells in asthmatic patients. Biochem Biophys Res Commun, 503:1557-1562.
23. Qiu YY, Wu Y, Lin MJ, et al (2019). LncRNA-MEG3 functions as a competing endogenous RNA to regulate Treg/Th17 balance in patients with asthma by targeting microRNA-17/ RORgammat. Biomed Pharmacother, 111:386-394.
24. Li X, Ye S, Lu Y (2020). Long non-coding RNA NEAT1 overexpression associates with increased exacerbation risk, severity, and inflammation, as well as decreased lung function through the interaction with microRNA-124 in asthma. J Clin Lab Anal, 34:e23023.
25. Jiang Y, Zhao Y, Mo X (2021). Expression of lncRNA NEAT1 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and its correlation with Th1/Th2 balance. Int J Clin Exp Pathol, 14:646-652.
26. Zhou RS, Zhang EX, Sun QF, Ye ZJ, Liu JW, Zhou DH, Tang Y (2019). Integrated analysis of lncRNA-miRNA-mRNA ceRNA network in squamous cell carcinoma of tongue. BMC Cancer, 19:779.
27. Duan XJ, Zhang X, Ding N, Zhang JY, Chen YP (2021). LncRNA NEAT1 regulates MMP-16 by targeting miR-200a/b to aggravate inflammation in asthma. Autoimmunity, 54:439-449.
28. Krug N, Hohlfeld JM, Kirsten AM, et al (2015). Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med, 372:1987-1995.
29. Gavitt TD, Hartmann AK, Sawant SS, Mara AB, Szczepanek SM, Rouge JL (2021). A GATA3 Targeting Nucleic Acid Nanocapsule for In Vivo Gene Regulation in Asthma. ACS Nano.
30. Ray A, Cohn L (1999). Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest, 104:985-993.
31. Yamashita N, Tashimo H, Ishida H, et al (2006). Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol, 290:L1045-1051.
32. Li W, Zhang Z, Liu X, Xiao C, Shang Y (2017). The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. J Clin Invest, 127:3421-3440.
| Files | ||
| Issue | Vol 52 No 1 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i1.11671 | |
| Keywords | ||
| Pediatric asthma Long noncoding RNAs Immunology Proteins | ||
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How to Cite
1.
Yan X, Liu H, Li T. Lncrna NEAT1 Regulates Th1/Th2 in Pediatric Asthma by Targeting Microrna-217/GATA3. Iran J Public Health. 2023;52(1):106-117.
