Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2018

Open Access 01-12-2018 | Research

Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics

Authors: Fatemeh Moheimani, Jorinke Koops, Teresa Williams, Andrew T. Reid, Philip M. Hansbro, Peter A. Wark, Darryl A. Knight

Published in: Respiratory Research | Issue 1/2018

Login to get access

Abstract

Background

Specific microRNAs (miRNAs) play essential roles in airway remodeling in asthma. Infection with influenza A virus (IAV) may also magnify pre-existing airway remodeling leading to asthma exacerbation. However, these events remain to be fully defined. We investigated the expression of miRNAs with diverse functions including proliferation (miR-20a), differentiation (miR-22) or innate/adaptive immune responses (miR-132) in primary bronchial epithelial cells (pBECs) of asthmatics following infection with the H1N1 strain of IAV.

Methods

pBECs from subjects (n = 5) with severe asthma and non-asthmatics were cultured as submerged monolayers or at the air-liquid-interface (ALI) conditions and incubated with IAV H1N1 (MOI 5) for up to 24 h. Isolated miRNAs were subjected to Taqman miRNAs assays. We confirmed miRNA targets using a specific mimic and antagomir. Taqman mRNAs assays and immunoblotting were used to assess expression of target genes and proteins, respectively.

Results

At baseline, these miRNAs were expressed at the same level in pBECs of asthmatics and non-asthmatics. After 24 h of infection, miR-22 expression increased significantly which was associated with the suppression of CD147 mRNA and HDAC4 mRNA and protein expression in pBECs from non-asthmatics, cultured in ALI. In contrast, miR-22 remained unchanged while CD147 expression increased and HDAC4 remained unaffected in cells from asthmatics. IAV H1N1 mediated increases in SP1 and c-Myc transcription factors may underpin the induction of CD147 in asthmatics.

Conclusion

The different profile of miR-22 expression in differentiated epithelial cells from non-asthmatics may indicate a self-defense mechanism against aberrant epithelial responses through suppressing CD147 and HDAC4, which is compromised in epithelial cells of asthmatics.
Appendix
Available only for authorised users
Literature
1.
2.
Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med. 2000;6:15–20.CrossRefPubMed
3.
Hallstrand TS, Hackett TL, Altemeier WA, Matute-Bello G, Hansbro PM, Knight DA. Airway epithelial regulation of pulmonary immune homeostasis and inflammation. Clin Immunol. 2014;151:1–15.CrossRefPubMed
4.
Hirota JA, Knight DA. Human airway epithelial cell innate immunity: relevance to asthma. Curr Opin Immunol. 2012;24:740–6.CrossRefPubMed
5.
Knight DA, Holgate ST. The airway epithelium: structural and functional properties in health and disease. Respirology. 2003;8:432–46.CrossRefPubMed
6.
Hackett TL, Singhera GK, Shaheen F, Hayden P, Jackson GR, Hegele RG, Van Eeden S, Bai TR, Dorscheid DR, Knight DA. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution. Am J Respir Cell Mol Biol. 2011;45:1090–100.CrossRefPubMed
7.
Kicic A, Sutanto EN, Stevens PT, Knight DA, Stick SM. Intrinsic biochemical and functional differences in bronchial epithelial cells of children with asthma. Am J Respir Crit Care Med. 2006;174:1110–8.CrossRefPubMed
8.
Cohen L, X E, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, DeMartino S, Schechtman KB, Hussain I, Holtzman MJ, et al. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med. 2007;176:138–45.CrossRefPubMedPubMedCentral
9.
Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, Holgate ST, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201:937–47.CrossRefPubMedPubMedCentral
10.
Warner SM, Hackett TL, Shaheen F, Hallstrand TS, Kicic A, Stick SM, Knight DA. Transcription factor p63 regulates key genes and wound repair in human airway epithelial basal cells. Am J Respir Cell Mol Biol. 2013;49:978–88.CrossRefPubMedPubMedCentral
11.
Roth HM, Wadsworth SJ, Kahn M, Knight DA. The airway epithelium in asthma: developmental issues that scar the airways for life? Pulm Pharmacol Ther. 2012;25:420–6.CrossRefPubMed
12.
Hsu AC, Barr I, Hansbro PM, Wark PA. Human influenza is more effective than avian influenza at antiviral suppression in airway cells. Am J Respir Cell Mol Biol. 2011;44:906–13.CrossRefPubMed
13.
Hsu AC, Parsons K, Barr I, Lowther S, Middleton D, Hansbro PM, Wark PA. Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection. PLoS One. 2012;7:e32947.CrossRefPubMedPubMedCentral
14.
15.
Travanty E, Zhou B, Zhang H, Di YP, Alcorn JF, Wentworth DE, Mason R, Wang J. Differential susceptibilities of human lung primary cells to H1N1 influenza viruses. J Virol. 2015;89:11935–44.CrossRefPubMedPubMedCentral
16.
Wanet A, Tacheny A, Arnould T, Renard P. miR-212/132 expression and functions: within and beyond the neuronal compartment. Nucleic Acids Res. 2012;40:4742–53.CrossRefPubMedPubMedCentral
17.
Martinez-Anton A, Sokolowska M, Kern S, Davis AS, Alsaaty S, Taubenberger JK, Sun J, Cai R, Danner RL, Eberlein M, et al. Changes in microRNA and mRNA expression with differentiation of human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2013;49:384–95.CrossRefPubMedPubMedCentral
18.
19.
Foster PS, Plank M, Collison A, Tay HL, Kaiko GE, Li J, Johnston SL, Hansbro PM, Kumar RK, Yang M, Mattes J. The emerging role of microRNAs in regulating immune and inflammatory responses in the lung. Immunol Rev. 2013;253:198–215.CrossRefPubMed
20.
Kim RY, Horvat JC, Pinkerton JW, Starkey MR, Essilfie AT, Mayall JR, Nair PM, Hansbro NG, Jones B, Haw TJ, et al. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J Allergy Clin Immunol. 2017;139:519–32.CrossRefPubMed
21.
Lu Y, Thomson JM, Wong HY, Hammond SM, Hogan BL. Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells. Dev Biol. 2007;310:442–53.CrossRefPubMedPubMedCentral
22.
Ahmad HM, Muiwo P, Ramachandran SS, Pandey P, Gupta YK, Kumar L, Kulshreshtha R, Bhattacharya A. miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1. FEBS J. 2014;281:3904–19.CrossRefPubMed
23.
Ting Y, Medina DJ, Strair RK, Schaar DG. Differentiation-associated miR-22 represses max expression and inhibits cell cycle progression. Biochem Biophys Res Commun. 2010;394:606–11.CrossRefPubMed
24.
25.
Lagos D, Pollara G, Henderson S, Gratrix F, Fabani M, Milne RS, Gotch F, Boshoff C. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat Cell Biol. 2010;12:513–9.CrossRefPubMed
26.
Buggele WA, Johnson KE, Horvath CM. Influenza A virus infection of human respiratory cells induces primary microRNA expression. J Biol Chem. 2012;287:31027–40.CrossRefPubMedPubMedCentral
27.
Lam WY, Yeung AC, Ngai KL, Li MS, To KF, Tsui SK, Chan PK. Effect of avian influenza A H5N1 infection on the expression of microRNA-141 in human respiratory epithelial cells. BMC Microbiol. 2013;13:104.CrossRefPubMedPubMedCentral
28.
Terrier O, Textoris J, Carron C, Marcel V, Bourdon JC, Rosa-Calatrava M. Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza a viruses reveal an unanticipated antiviral activity for miR-146a. J Gen Virol. 2013;94:985–95.CrossRefPubMed
29.
Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–73.CrossRefPubMed
30.
Hurd SZ, Workshop summary and guidelines: investigative use of bronchoscopy, lavage, and bronchial biopsies in asthma and other airway diseases. J Allergy Clin Immunol 1991;88:808–14.CrossRef
31.
Hackett TL, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, Argentieri R, Kicic A, Stick SM, Bai TR, Knight DA. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med. 2009;180:122–33.CrossRefPubMed
32.
Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y, Pollack J, Peyton M, Zou Y, Kurie JM, Dimaio JM, et al. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 2004;64:9027–34.CrossRefPubMed
33.
Moheimani F, Roth HM, Cross J, Reid AT, Shaheen F, Warner SM, Hirota JA, Kicic A, Hallstrand TS, Kahn M, et al. Disruption of beta-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair. Int J Biochem Cell Biol. 2015;68:59–69.CrossRefPubMed
34.
Huprikar J, Rabinowitz S. A simplified plaque assay for influenza viruses in Madin-Darby kidney (MDCK) cells. J Virol Methods. 1980;1:117–20.CrossRefPubMed
35.
Hsu AC, Parsons K, Moheimani F, Knight DA, Hansbro PM, Fujita T, Wark PA. Impaired antiviral stress granule and IFN-beta enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium. Am J Respir Cell Mol Biol. 2016;55:117–27.CrossRefPubMed
36.
Brown BE, Dean RT, Davies MJ. Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells. Diabetologia. 2005;48:361–9.CrossRefPubMed
37.
Baker JR, Vuppusetty C, Colley T, Papaioannou AI, Fenwick P, Donnelly L, Ito K, Barnes PJ. Oxidative stress dependent microRNA-34a activation via PI3Kalpha reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. Sci Rep. 2016;6:35871.CrossRefPubMedPubMedCentral
38.
Martinez-Nunez RT, Bondanese VP, Louafi F, Francisco-Garcia AS, Rupani H, Bedke N, Holgate S, Howarth PH, Davies DE, Sanchez-Elsner T. A microRNA network dysregulated in asthma controls IL-6 production in bronchial epithelial cells. PLoS One. 2014;9:e111659.CrossRefPubMedPubMedCentral
39.
Williams AE, Larner-Svensson H, Perry MM, Campbell GA, Herrick SE, Adcock IM, Erjefalt JS, Chung KF, Lindsay MA. MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS One. 2009;4:e5889.CrossRefPubMedPubMedCentral
40.
Banda M, Bommineni A, Thomas RA, Luckinbill LS, Tucker JD. Evaluation and validation of housekeeping genes in response to ionizing radiation and chemical exposure for normalizing RNA expression in real-time PCR. Mutat Res. 2008;649:126–34.CrossRefPubMed
41.
Kuchipudi SV, Tellabati M, Nelli RK, White GA, Perez BB, Sebastian S, Slomka MJ, Brookes SM, Brown IH, Dunham SP, Chang KC. 18S rRNA is a reliable normalisation gene for real time PCR based on influenza virus infected cells. Virol J. 2012;9:230.CrossRefPubMedPubMedCentral
42.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRefPubMed
43.
Yao PM, Buhler JM, d'Ortho MP, Lebargy F, Delclaux C, Harf A, Lafuma C. Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial cells from human bronchial explants. J Biol Chem. 1996;271:15580–9.CrossRefPubMed
44.
Walters MS, Gomi K, Ashbridge B, Moore MA, Arbelaez V, Heldrich J, Ding BS, Rafii S, Staudt MR, Crystal RG. Generation of a human airway epithelium derived basal cell line with multipotent differentiation capacity. Respir Res. 2013;14:135.CrossRefPubMedPubMedCentral
45.
Stewart CE, Torr EE, Mohd Jamili NH, Bosquillon C, Sayers I. Evaluation of differentiated human bronchial epithelial cell culture systems for asthma research. J Allergy (Cairo). 2012;2012:943982.
46.
Hamilton SB, Wyatt DE, Wahlgren BT, O'Dowd MK, Morrissey JM, Daniels DE, Lednicky JA. Higher titers of some H5N1 and recent human H1N1 and H3N2 influenza viruses in Mv1 Lu vs. MDCK cells. Virol J. 2011;8:66.CrossRefPubMedPubMedCentral
47.
Lu W, You R, Yuan X, Yang T, Samuel EL, Marcano DC, Sikkema WK, Tour JM, Rodriguez A, Kheradmand F, Corry DB. The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell-dependent emphysema. Nat Immunol. 2015;16:1185–94.CrossRefPubMedPubMedCentral
48.
Jouneau S, Khorasani N, De Souza P, Macedo P, Zhu J, Bhavsar PK, Chung KF. EMMPRIN (CD147) regulation of MMP-9 in bronchial epithelial cells in COPD. Respirology. 2011;16:705–12.CrossRefPubMed
49.
Park IH, Kang JH, Shin JM, Lee HM. Trichostatin a inhibits epithelial mesenchymal transition induced by TGF-beta1 in airway epithelium. PLoS One. 2016;11:e0162058.CrossRefPubMedPubMedCentral
50.
Li LF, Lee CS, Lin CW, Chen NH, Chuang LP, Hung CY, Liu YY. Trichostatin a attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway. PLoS One. 2017;12:e0172571.CrossRefPubMedPubMedCentral
51.
Tacon CE, Wiehler S, Holden NS, Newton R, Proud D, Leigh R. Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B. Am J Respir Cell Mol Biol. 2010;43:201–9.CrossRefPubMed
52.
Cho JY, Miller M, McElwain K, McElwain S, Shim JY, Raz E, Broide DH. Remodeling associated expression of matrix metalloproteinase 9 but not tissue inhibitor of metalloproteinase 1 in airway epithelium: modulation by immunostimulatory DNA. J Allergy Clin Immunol. 2006;117:618–25.CrossRefPubMed
53.
Kong LM, Liao CG, Zhang Y, Xu J, Li Y, Huang W, Zhang Y, Bian H, Chen ZN. A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res. 2014;74:3764–78.CrossRefPubMed
54.
Liu F, Pore N, Kim M, Voong KR, Dowling M, Maity A, Kao GD. Regulation of histone deacetylase 4 expression by the SP family of transcription factors. Mol Biol Cell. 2006;17:585–97.CrossRefPubMedPubMedCentral
55.
Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, Haitchi HM, Vernon-Wilson E, Sammut D, Bedke N, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol. 2011;128:549–56. e541–512CrossRefPubMed
56.
Fujimoto Y, Hasegawa S, Matsushige T, Wakiguchi H, Nakamura T, Hasegawa H, Nakajima N, Ainai A, Oga A, Itoh H, et al. Pulmonary inflammation and cytokine dynamics of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during A(H1N1)pdm09 influenza infection. Sci Rep. 2017;7:9128.CrossRefPubMedPubMedCentral
57.
Investigators AI, Webb SA, Pettila V, Seppelt I, Bellomo R, Bailey M, Cooper DJ, Cretikos M, Davies AR, Finfer S, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med. 2009;361:1925–34.CrossRef
58.
Haj-Salem I, Fakhfakh R, Berube JC, Jacques E, Plante S, Simard MJ, Bosse Y, Chakir J. MicroRNA-19a enhances proliferation of bronchial epithelial cells by targeting TGFbetaR2 gene in severe asthma. Allergy. 2015;70:212–9.CrossRefPubMed
59.
Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C, Barczak AJ, et al. Airway epithelial miRNA expression is altered in asthma. Am J Respir Crit Care Med. 2012;186:965–74.CrossRefPubMedPubMedCentral
60.
Mattos W, Lim S, Russell R, Jatakanon A, Chung KF, Barnes PJ. Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest. 2002;122:1543–52.CrossRefPubMed
61.
62.
Banerjee B, Musk M, Sutanto EN, Yerkovich ST, Hopkins P, Knight DA, Lindsey-Temple S, Stick SM, Kicic A, Chambers DC. Regional differences in susceptibiity of bronchial epithelium to mesenchymal transition and inhibition by the macrolide antibiotic azithromycin. PLoS One. 2012;7:e52309.CrossRefPubMedPubMedCentral
63.
Farhat AA, Mohamad AS, Shareef MM, Atef Attia G, Eid MA, Taha RW. Asthma remodeling: the pathogenic role of matrix metalloproteinase-9. Egypt J Chest Dis Tuberc. 2014;63:755–9.CrossRef
Metadata
Title
Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics
Authors
Fatemeh Moheimani
Jorinke Koops
Teresa Williams
Andrew T. Reid
Philip M. Hansbro
Peter A. Wark
Darryl A. Knight
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-018-0851-7

Other articles of this Issue 1/2018

Respiratory Research 1/2018 Go to the issue

Research

Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study

Letter to the Editor

Carbon monoxide levels after inhalation from new generation heated tobacco products

Research

Efficacy and safety of nintedanib in advanced idiopathic pulmonary fibrosis

Research

Serum metabolic profiling identified a distinct metabolic signature in patients with idiopathic pulmonary fibrosis – a potential biomarker role for LysoPC

Letter to the Editor

Commenting on “Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from ACE 2 study” by Jacob A. Winther and colleagues

Research

Relationship of CT-quantified emphysema, small airways disease and bronchial wall dimensions with physiological, inflammatory and infective measures in COPD

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits