Original Article
 

Analysis of Differentially Expressed MicroRNAs in OVA-induced Airway Remodeling Model Mice

Abstract

MicroRNAs (miRNAs) can participate in airway remodeling by regulating immune molecule expression. Here, we aimed to identify the differential miRNAs involved in airway remodeling.
Airway remodeling was induced by ovalbumin in female BALB/C mice. The differentially expressed miRNAs were screened with microarray. GO (Gene Ontology) and KEGG enrichment analysis was performed. The miRNA target gene network and miRNA target pathway network were constructed. Verification with real-time PCR and Western blot was performed.
We identified 63 differentially expressed miRNAs (50 up-regulated and 13 down-regulated) in the lungs of ovalbumin-induced airway remodeling mice. Real-time PCR confirmed that 3 miRNAs (mmu-miR-1931, mmu-miR-712-5p, and mmu-miR-770-5p) were significantly up-regulated, and 4 miRNAs (mmu-miR-128-3p, mmu-miR-182-5p, mmu-miR-130b-3p, and mmu-miR-20b-5p) were significantly down-regulated. The miRNA target gene network analysis identified key mRNAs in the airway remodeling, such as Tnrc6b (trinucleotide repeat containing adaptor 6B), Sesn3 (sestrin 3), Baz2a (bromodomain adjacent to zinc finger domain 2a), and Cux1 (cut like homeobox 1). The miRNA target pathway network showed that the signal pathways such as MAPK (mitogen-activated protein kinase), PI3K/Akt (phosphoinositide 3-Kinase/protein kinase B), p53 (protein 53), and mTOR (mammalian target of rapamycin) were closely related to airway remodeling in asthma.
Collectively, differential miRNAs involved in airway remodeling (such as mmu-miR-1931, mmu-miR-712-5p, mmu-miR-770-5p, mmu-miR-128-3p mmu-miR-182-5p, and mmu-miR-130b-3p) as well as their target genes (such as Tnrc6b, Sesn3, Baz2a, and Cux1) and pathways (such as MAPK, PI3K/Akt, p53, mTOR pathways) have been identified. Our findings may help to further understand the pathogenesis of airway remodeling.

1. Cheng SL. Immunologic Pathophysiology and Airway Remodeling Mechanism in Severe Asthma: Focused on IgE-Mediated Pathways. Diagnostics. 2021;11(1):83.
2. Sudini K, Diette GB, Breysse PN, McCormack MC, Bull D, Biswal S, et al. A Randomized Controlled Trial of the Effect of Broccoli Sprouts on Antioxidant Gene Expression and Airway Inflammation in Asthmatics. J Allergy Clin Immunol Pract. 2016;4(5):932-40.
3. Samanta S, Balasubramanian S, Rajasingh S, Patel U, Dhanasekaran A, Dawn B, et al. MicroRNA: A new therapeutic strategy for cardiovascular diseases. Trends Cardiovasc Med. 2016;26(5):407-19.
4. Xiao Q, Zhang N, Luo J, Dai J, Tang X. Adaptive multi-source multi-view latent feature learning for inferring potential disease-associated miRNAs. Brief Bioinform. 2021;22(2):2043-57.
5. Meningher T, Barsheshet Y, Ofir-Birin Y, Gold D, Brant B, Dekel E, et al. Schistosomal extracellular vesicle-enclosed miRNAs modulate host T helper cell differentiation. EMBO reports. 2020;21(1):e47882.
6. Roy S, Awasthi A. Emerging roles of noncoding RNAs in T cell differentiation and functions in autoimmune diseases. Int Rev Immunol. 2019;38(5):232-45.
7. Singh P, Sharma A, Jha R, Arora S, Ahmad R, Rahmani AH, et al. Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma. Sci Rep. 2020;10(1):13354.
8. Shi J, Chen M, Ouyang L, Wang Q, Guo Y, Huang L, et al. MiR-142-5p and miR-130a-3p regulate pulmonary macrophage polarization and asthma airway remodeling. Immunol Cell Biol. 2020;98(9):715-25.
9. Shao Y, Chong L, Lin P, Li H, Zhu L, Wu Q, et al. MicroRNA-133a alleviates airway remodeling in asthtama through PI3K/AKT/mTOR signaling pathway by targeting IGF1R. J Cell Physiol. 2019;234(4):4068-80.
10. Wang Y, Guan J, Wang Y. Could microRNA be used as a diagnostic tool for lung cancer? J Cell Biochem. 2019;120(11):18937-45.
11. Liu Y, Chen Z, Xu K, Wang Z, Wu C, Sun Z, et al. Next generation sequencing for miRNA profile of spleen CD4(+) T cells in the murine model of acute asthma. Epigenomics. 2018;10(8):1071-83.
12. Ntontsi P, Photiades A, Zervas E, Xanthou G, Samitas K. Genetics and Epigenetics in Asthma. Int J Mol Sci. 2021;22(5):2412.
13. Oliveria JP, Agayby R, Gauvreau GM. Regulatory and IgE+ B Cells in Allergic Asthma. Methods Mol Biol. 2021;2270:375-418.
14. Zhang Z, Wang J, Chen O. Identification of biomarkers and pathogenesis in severe asthma by coexpression network analysis. BMC Med Genomics. 2021;14(1):51.
15. Ding L, Gao X, Yu S, Sheng L. MiR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14. J Bioenerg Biomembr. 2020;52(4):237-45.
16. Dang X, He B, Ning Q, Liu Y, Chang Y, Chen M. Suppression of TRIM8 by microRNA-182-5p restricts tumor necrosis factor-alpha-induced proliferation and migration of airway smooth muscle cells through inactivation of NF-Kb. Int Immunopharmacol. 2020;83:106475.
17. Li S, Geng J, Xu X, Huang X, Leng D, Jiang D, et al. MiR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1. PloS One. 2016;11(3):e0150418.
18. Tai L, Huang CJ, Choo KB, Cheong SK, Kamarul T. Oxidative Stress Down-Regulates MiR-20b-5p, MiR-106a-5p and E2F1 Expression to Suppress the G1/S Transition of the Cell Cycle in Multipotent Stromal Cells. Int J Med Sci. 2020;17(4):457-70.
19. Lu L, McCurdy S, Huang S, Zhu X, Peplowska K, Tiirikainen M, et al. Time Series miRNA-mRNA integrated analysis reveals critical miRNAs and targets in macrophage polarization. Sci Rep. 2016;6:37446.
20. Fuentes N, Roy A, Mishra V, Cabello N, Silveyra P. Sex-specific microRNA expression networks in an acute mouse model of ozone-induced lung inflammation. Biol Sex Differ. 2018;9(1):18.
21. Yuan J, Li P, Pan H, Xu Q, Xu T, Li Y, et al. MiR-770-5p inhibits the activation of pulmonary fibroblasts and silica-induced pulmonary fibrosis through targeting TGFBR1. Ecotoxicol Environ Saf. 2021;220:112372.
22. Caramori G, Casolari P, Adcock I. Role of transcription factors in the pathogenesis of asthma and COPD. Cell Commun Adhes. 2013;20(1-2):21-40.
23. Ohno I. Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation. Allergol Int. 2017;66S:S2-S8.
24. Boulet LP. Airway remodeling in asthma: update on mechanisms and therapeutic approaches. Curr Opin Pulm Med. 2018;24(1):56-62.
25. Zhao J, Dar HH, Deng Y, St Croix CM, Li Z, Minami Y, Shrivastava IH, Tyurina YY, Etling E, Rosenbaum JC, Nagasaki T, Trudeau JB, Watkins SC, Bahar I, Bayır H, VanDemark AP, Kagan VE, Wenzel SE. PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells. Proc Natl Acad Sci U S A. 2020;117(25):14376-14385.
26. Lewenstam A. Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta. 2000;294(1-2):1-26.
27. Adcock IM, Lane SJ, Brown CR, Peters MJ, Lee TH, Barnes PJ. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol. 1995;154(7):3500-5.
28. Yang Y, Li X, An X, Zhang L, Li X, Wang L, Zhu G. Continuous exposure of PM2.5 exacerbates ovalbumin-induced asthma in mouse lung via a JAK-STAT6 signaling pathway. Adv Clin Exp Med. 2020;29(7):825-832.
29. Ha H, Debnath B, Neamati N. Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. Theranostics. 2017;7(6):1543-1588.
30. Hachim MY, Elemam NM, Ramakrishnan RK, Bajbouj K, Olivenstein R, Hachim IY, Al Heialy S, Hamid Q, Busch H, Hamoudi R. Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts. Front Cell Dev Biol. 2021;9:641404.
31. Zhang Y, Jing Y, Qiao J, Luan B, Wang X, Wang L, Song Z. Activation of the mTOR signaling pathway is required for asthma onset. Sci Rep. 2017;7(1):4532-9.
32. Pan HH, Hsiao YP, Chen PJ, Kang YT, Chao YH, Sheu JN, Lue KH, Ko JL. Epithelial growth factor receptor tyrosine kinase inhibitors alleviate house dust mite allergen Der p2-induced IL-6 and IL-8. Environ Toxicol. 2019 ;34(4):476-85.
33. Zhou J, Zhang N, Zhang W, Lu C, Xu F. The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell differentiation. Cell Biosci. 2021;11(1):84-9.
34. Deshpande DA, Guedes AGP, Graeff R, Dogan S, Subramanian S, Walseth TF, Kannan MS. CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms. Mediators Inflamm. 2018;2018:8942042.
35. McGraw DW, Fogel KM, Kong S, Litonjua AA, Kranias EG, Aronow BJ, Liggett SB. Transcriptional response to persistent beta2-adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility. Physiol Genomics. 2006;27(2):171-7.
36. Fang SB, Zhang HY, Jiang AY, Fan XL, Lin YD, Li CL, Wang C, Meng XC, Fu QL. Human iPSC-MSCs prevent steroid-resistant neutrophilic airway inflammation via modulating Th17 phenotypes. Stem Cell Res Ther. 2018;9(1):147.
37. Wei EQ, Irie Y, Kuo CH, Ding Y, Niu SY, Do E, Miki N. A single stranded DNA-binding protein, ssCRE-BP/Pur alpha, in rat lung and its increase in allergic airway inflammation. Jpn J Pharmacol. 1998;78(4):419-27.
38. Sheu-Gruttadauria J, MacRae IJ. Phase Transitions in the Assembly and Function of Human miRISC. Cell. 2018;173(4):946-57.
39. Wang M, Xu Y, Liu J, Ye J, Yuan W, Jiang H, et al. Recent Insights into the Biological Functions of Sestrins in Health and Disease. Cell Physiol Biochem. 2017;43(5):1731-41.
40. Zhang J, Ng S, Wang J, Zhou J, Tan SH, Yang N, et al. Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways. Autophagy. 2015;11(4):629-42.
41. Dalle Vedove A, Spiliotopoulos D, D'Agostino VG, Marchand JR, Unzue A, Nevado C, et al. Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains. ChemMedChem. 2018;13(14):1479-87.
42. Ikeda T, Fragiadaki M, Shi-Wen X, Ponticos M, Khan K, Denton C, et al. Transforming growth factor-β-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts. Biochem Biophys Rep. 2016;7:246-52.
43. Imgruet MK, Lutze J, An NN, Hu B, Khan S, Kurkewich J, et al. Loss of a 7q gene, CUX1, disrupts epigenetic-driven DNA repair and drives therapy-related myeloid neoplasms. Blood. 2021;138(9):790-805.
44. Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, et al. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet. 2014;46(1):33-8.
45. Feng S, Ding H, Liu L, Peng C, Huang Y, Zhong F, et al. Astragalus polysaccharide enhances the immune function of RAW264.7 macrophages via the NF-κB p65/MAPK signaling pathway. Exp Ther Med. 2021;21(1):20-8.
46. Song Y, Wang Z, Jiang J, Piao Y, Li L, Xu C, et al. DEK-targeting aptamer DTA-64 attenuates bronchial EMT-mediated airway remodelling by suppressing TGF-beta1/Smad, MAPK and PI3K signalling pathway in asthma. J Cell Mol Med. 2020;24(23):13739-50.
47. Zhao Y, Li X, Xu Z, Hao L, Zhang Y, Liu Z. PI3K-AKT-mTOR signaling pathway: the intersection of allergic asthma and cataract. Pharmazie. 2019;74(10):598-600.
48. Hernandez Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188556.
49. Trian T, Allard B, Ozier A, Maurat E, Dupin I, Thumerel M, et al. Selective dysfunction of p53 for mitochondrial biogenesis induces cellular proliferation in bronchial smooth muscle from asthmatic patients. J Allergy Clin Immunol. 2016;137(6):1717-26.
50. Wang S, Wuniqiemu T, Tang W, Teng F, Bian Q, Yi, et al. Luteolin inhibits autophagy in allergic asthma by activating PI3K/Akt/mTOR signaling and inhibiting Beclin-1-PI3KC3 complex. Int Immunopharmacol. 2021;94:107460.
Files
IssueVol 21 No 5 (2022) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v21i5.11040
Keywords
Airway remodeling Computational biology MicroRNAs Microarray analysis

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Xu C, Song Y, Wang C, Jiang J, Wang Z, Li L, Yan G. Analysis of Differentially Expressed MicroRNAs in OVA-induced Airway Remodeling Model Mice. Iran J Allergy Asthma Immunol. 2022;21(5):524-536.