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MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

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Abstract

Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNA-target interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD.

Key messages

  • Histone deacetylase 2 is directly targeted by miR-223.

  • Levels of miR-223 are induced by interleukin-1β and tumor necrosis factor-α.

  • miR-223 controls the expression of fractalkine by targeting histone deacetylase 2.

  • miR-223 levels are increased in COPD mouse models.

  • miR-223 levels inversely correlate with HDAC2 expression in COPD patients.

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References

  1. Raherison C, Girodet PO (2009) Epidemiology of COPD. Eur Respir Rev 18:213–221

    Article  CAS  PubMed  Google Scholar 

  2. Gan WQ, Man SF, Senthilselvan A, Sin DD (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59:574–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P et al (2009) Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 136:678–687

    Article  CAS  PubMed  Google Scholar 

  4. Rius C, Company C, Piqueras L, Cerda-Nicolas JM, Gonzalez C, Servera E, Ludwig A, Morcillo EJ, Sanz MJ (2013) Critical role of fractalkine (CX3CL1) in cigarette smoke-induced mononuclear cell adhesion to the arterial endothelium. Thorax 68:177–186

    Article  PubMed  Google Scholar 

  5. Chung KF, Adcock IM (2008) Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J 31:1334–1356

    Article  CAS  PubMed  Google Scholar 

  6. Urnov FD, Wolffe AP (2001) Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene 20:2991–3006

    Article  CAS  PubMed  Google Scholar 

  7. Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25:552–563

    Article  CAS  PubMed  Google Scholar 

  8. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC et al (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352:1967–1976

    Article  CAS  PubMed  Google Scholar 

  9. Noh JH, Chang YG, Kim MG, Jung KH, Kim JK, Bae HJ, Eun JW, Shen Q, Kim SJ, Kwon SH et al (2013) MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett 335:455–462

    Article  CAS  PubMed  Google Scholar 

  10. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lapperre TS, Snoeck-Stroband JB, Gosman MM, Jansen DF, van Schadewijk A, Thiadens HA, Vonk JM, Boezen HM, Ten Hacken NH, Sont JK et al (2009) Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 151:517–527

    Article  PubMed  Google Scholar 

  13. Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, Xiao J, Zhang X, Duclos G, Drizik E et al (2013) A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med 187:933–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. van den Berge M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev YO, Lenburg ME, Spira A et al (2014) Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax 69:14–23

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122:1954–1966

    Article  CAS  PubMed  Google Scholar 

  16. Engler A, Niederer F, Klein K, Gay RE, Kyburz D, Camici GG, Gay S, Ospelt C (2014) SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts. J Mol Med 92:757–767

    Article  CAS  PubMed  Google Scholar 

  17. Hakansson HF, Smailagic A, Brunmark C, Miller-Larsson A, Lal H (2012) Altered lung function relates to inflammation in an acute LPS mouse model. Pulm Pharmacol Ther 25:399–406

    Article  PubMed  Google Scholar 

  18. Dweep H, Sticht C, Pandey P, Gretz N (2011) miRWalk—database: prediction of possible miRNA binding sites by "walking" the genes of three genomes. J Biomed Inform 44:839–847

    Article  CAS  PubMed  Google Scholar 

  19. Osoata GO, Yamamura S, Ito M, Vuppusetty C, Adcock IM, Barnes PJ, Ito K (2009) Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophys Res Commun 384:366–371

    Article  CAS  PubMed  Google Scholar 

  20. Min T, Bodas M, Mazur S, Vij N (2011) Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med 89:577–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ezzie ME, Crawford M, Cho JH, Orellana R, Zhang S, Gelinas R, Batte K, Yu L, Nuovo G, Galas D et al (2012) Gene expression networks in COPD: microRNA and mRNA regulation. Thorax 67:122–131

    Article  PubMed  Google Scholar 

  22. Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, Ulrich S, Speich R, Huber LC (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104:1184–1191

    Article  CAS  PubMed  Google Scholar 

  23. Barnes PJ (2009) The cytokine network in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 41:631–638

    Article  CAS  PubMed  Google Scholar 

  24. Chung S, Sundar IK, Hwang JW, Yull FE, Blackwell TS, Kinnula VL, Bulger M, Yao H, Rahman I (2011) NF-kappaB inducing kinase, NIK mediates cigarette smoke/TNFalpha-induced histone acetylation and inflammation through differential activation of IKKs. PLoS One 6, e23488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ismail N, Wang Y, Dakhlallah D, Moldovan L, Agarwal K, Batte K, Shah P, Wisler J, Eubank TD, Tridandapani S et al (2013) Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 121:984–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Clarenbach CF, Senn O, Sievi NA, Camen G, van Gestel AJ, Rossi VA, Puhan MA, Thurnheer R, Russi EW, Kohler M (2013) Determinants of endothelial function in patients with COPD. Eur Respir J 42:1194–1204

    Article  CAS  PubMed  Google Scholar 

  27. Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KA, Boon NA, Webb DJ (1999) Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 99:1411–1415

    Article  CAS  PubMed  Google Scholar 

  28. Zhang J, Patel JM (2010) Role of the CX3CL1-CX3CR1 axis in chronic inflammatory lung diseases. Int J Clin Exp Med 3:233–244

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ludwig A, Weber C (2007) Transmembrane chemokines: versatile ‘special agents’ in vascular inflammation. Thromb Haemost 97:694–703

    CAS  PubMed  Google Scholar 

  30. Barnes PJ (2009) Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:693–696

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Michaela Kirschner for critical reading of the manuscript. Main sponsor: the Swiss Lung Association (LLS-no. 2014-09). This work was further supported by the Olga Mayenfisch Foundation and the Swiss National Science Foundation (SNF grant no. 31003A_144212).

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Authors and Affiliations

  1. Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Caroline Leuenberger, Claudio Schuoler, Hannah Bye, Célia Mignan, Thomas Rechsteiner, Malcolm Kohler, Lars C. Huber & Matthias Brock

  2. Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland

    Claudio Schuoler

  3. Division of Thoracic Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Sven Hillinger & Isabelle Opitz

  4. Faculty of Biology and Medicine, Service de Pneumologie, University of Lausanne, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Benjamin Marsland

  5. Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Alen Faiz

  6. Department of Pulmonary Diseases, Leiden University Medical Center, Leiden, The Netherlands

    Pieter S. Hiemstra

  7. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Wim Timens

  8. Center for Molecular Cardiology, Division of Cardiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

    Giovanni G. Camici

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  1. Caroline Leuenberger
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  2. Claudio Schuoler
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  3. Hannah Bye
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  4. Célia Mignan
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  6. Sven Hillinger
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  7. Isabelle Opitz
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  8. Benjamin Marsland
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  9. Alen Faiz
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  10. Pieter S. Hiemstra
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  11. Wim Timens
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  12. Giovanni G. Camici
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  13. Malcolm Kohler
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  14. Lars C. Huber
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  15. Matthias Brock
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Correspondence to Matthias Brock.

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Lars C. Huber and Matthias Brock share senior authorship.

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Leuenberger, C., Schuoler, C., Bye, H. et al. MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD. J Mol Med 94, 725–734 (2016). https://doi.org/10.1007/s00109-016-1388-1

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  • DOI: https://doi.org/10.1007/s00109-016-1388-1

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