Advertisement

Inflammation

pp 1–10 | Cite as

MicroRNA-30a Targets ATG5 and Attenuates Airway Fibrosis in Asthma by Suppressing Autophagy

  • Bin Bin Li
  • Yun long ChenEmail author
  • Fuzhen PangEmail author
Original Article
First Online:
  • 47 Downloads

Abstract

Asthma is the most common chronic disease of childhood, chronic airway inflammation; bronchial tissue fibrosis, is a pathological feature common to children asthma, and an emerging data has indicted that autophagy plays critical roles in airway inflammation and fibrosis-mediated airway remodeling. The aim of this study was to examine whether the antifibrotic effect of epithelial microRNAs (miRNAs) relies on regulating autophagy-mediated airway remodeling and to identify the factors involved and the underlying mechanisms. Our results showed miR-30a were downregulated in children with asthma and ovalbumin (OVA) mouse model in parallel with the upregulation of autophagy-related proteins; moreover, we observed miR-30a inhibited the autophagy by downregulated autophagy-related 5 (ATG5). Then, we observed that overexpression of miR-30a suppressed the fibrogenesis and autophagic flux which was stimulated by interleukin-33 (IL-33) in bronchial epithelial cells. In vivo experiments showed that miR-30a overexpression decreased airway remodeling by decreased autophagy. This study uncovered a previously unrecognized antifibrotic role of miR-30a in asthma, in IL-33-induced lung epithelial cells in vitro, and in a murine model of OVA-induced airway inflammation in vivo and explored the underlying mechanisms.

KEY WORDS

miR-30a ATG5 Autophagy Airway fibrosis Asthma 
This is a preview of subscription content, log in to check access.

Notes

Compliance with Ethical Standards

All mouse experiments were approved by research committee of Zhejiang University. This study was approved by the Hangzhou Children’s Hospital and written informed consent was obtained from all patients.

References

  1. 1.
    Holgate, S.T. 2008. The airway epithelium is central to the pathogenesis of asthma. Allergology International 57 (1): 1–10.CrossRefGoogle Scholar
  2. 2.
    Holgate, S.T. 2008. Pathogenesis of asthma. Clinical and Experimental Allergy 38 (6): 872–897.CrossRefGoogle Scholar
  3. 3.
    Poe, C.A., and S. Johnson. 1972. Psychologists’ conception of optimal adjustment. Journal of Clinical Psychology 28 (4): 449–451.CrossRefGoogle Scholar
  4. 4.
    Papi, A., C. Brightling, S.E. Pedersen, and H.K. Reddel. 2018. Asthma. Lancet. 391 (10122): 783–800.CrossRefGoogle Scholar
  5. 5.
    Lopez, E., V. del Pozo, T. Miguel, B. Sastre, C. Seoane, E. Civantos, et al. 2006. Inhibition of chronic airway inflammation and remodeling by galectin-3 gene therapy in a murine model. Journal of Immunology 176 (3): 1943–1950.CrossRefGoogle Scholar
  6. 6.
    Chan, V., J.K. Burgess, J.C. Ratoff, B.J. O'Connor, A. Greenough, T.H. Lee, and S.J. Hirst. 2006. Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. American Journal of Respiratory and Critical Care Medicine 174 (4): 379–385.CrossRefGoogle Scholar
  7. 7.
    Yick, C.Y., D.S. Ferreira, R. Annoni, J.H. von der Thusen, P.W. Kunst, E.H. Bel, et al. 2012. Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma. Allergy 67 (4): 552–559.CrossRefGoogle Scholar
  8. 8.
    Gudbjartsson, D.F., U.S. Bjornsdottir, E. Halapi, A. Helgadottir, P. Sulem, G.M. Jonsdottir, G. Thorleifsson, H. Helgadottir, V. Steinthorsdottir, H. Stefansson, C. Williams, J. Hui, J. Beilby, N.M. Warrington, A. James, L.J. Palmer, G.H. Koppelman, A. Heinzmann, M. Krueger, H.M. Boezen, A. Wheatley, J. Altmuller, H.D. Shin, S.T. Uh, H.S. Cheong, B. Jonsdottir, D. Gislason, C.S. Park, L.M. Rasmussen, C. Porsbjerg, J.W. Hansen, V. Backer, T. Werge, C. Janson, U.B. Jönsson, M.C.Y. Ng, J. Chan, W.Y. So, R. Ma, S.H. Shah, C.B. Granger, A.A. Quyyumi, A.I. Levey, V. Vaccarino, M.P. Reilly, D.J. Rader, M.J.A. Williams, A.M. van Rij, G.T. Jones, E. Trabetti, G. Malerba, P.F. Pignatti, A. Boner, L. Pescollderungg, D. Girelli, O. Olivieri, N. Martinelli, B.R. Ludviksson, D. Ludviksdottir, G.I. Eyjolfsson, D. Arnar, G. Thorgeirsson, K. Deichmann, P.J. Thompson, M. Wjst, I.P. Hall, D.S. Postma, T. Gislason, J. Gulcher, A. Kong, I. Jonsdottir, U. Thorsteinsdottir, and K. Stefansson. 2009. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nature Genetics 41 (3): 342–347.CrossRefGoogle Scholar
  9. 9.
    Bianchetti, L., M.A. Marini, M. Isgro, A. Bellini, M. Schmidt, and S. Mattoli. 2012. IL-33 promotes the migration and proliferation of circulating fibrocytes from patients with allergen-exacerbated asthma. Biochemical and Biophysical Research Communications 426 (1): 116–121.CrossRefGoogle Scholar
  10. 10.
    Malaviya, R., J.D. Laskin, and D.L. Laskin. 2017. Anti-TNF alpha therapy in inflammatory lung diseases. Pharmacology & Therapeutics 180: 90–98.CrossRefGoogle Scholar
  11. 11.
    Cayrol, C., A. Duval, P. Schmitt, S. Roga, M. Camus, A. Stella, O. Burlet-Schiltz, A. Gonzalez-de-Peredo, and J.P. Girard. 2018. Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nature Immunology 19 (4): 375–385.CrossRefGoogle Scholar
  12. 12.
    Suzuki, K., T. Kirisako, Y. Kamada, N. Mizushima, T. Noda, and Y. Ohsumi. 2001. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. The EMBO Journal 20 (21): 5971–5981.CrossRefGoogle Scholar
  13. 13.
    Jounai, N., F. Takeshita, K. Kobiyama, A. Sawano, A. Miyawaki, K.Q. Xin, K.J. Ishii, T. Kawai, S. Akira, K. Suzuki, and K. Okuda. 2007. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proceedings of the National Academy of Sciences of the United States of America 104 (35): 14050–14055.CrossRefGoogle Scholar
  14. 14.
    Araya, J., J. Kojima, N. Takasaka, S. Ito, S. Fujii, H. Hara, H. Yanagisawa, K. Kobayashi, C. Tsurushige, M. Kawaishi, N. Kamiya, J. Hirano, M. Odaka, T. Morikawa, S.L. Nishimura, Y. Kawabata, H. Hano, K. Nakayama, and K. Kuwano. 2013. Insufficient autophagy in idiopathic pulmonary fibrosis. American Journal of Physiology Lung Cellular and Molecular Physiology 304 (1): L56–L69.CrossRefGoogle Scholar
  15. 15.
    Hernandez-Gea, V., Z. Ghiassi-Nejad, R. Rozenfeld, R. Gordon, M.I. Fiel, Z. Yue, et al. 2012. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142 (4): 938–946.CrossRefGoogle Scholar
  16. 16.
    Poon, A.H., F. Chouiali, S.M. Tse, A.A. Litonjua, S.N. Hussain, C.J. Baglole, et al. 2012. Genetic and histologic evidence for autophagy in asthma pathogenesis. The Journal of Allergy and Clinical Immunology 129 (2): 569–571.CrossRefGoogle Scholar
  17. 17.
    Martin, L.J., J. Gupta, S.S. Jyothula, M. Butsch Kovacic, J.M. Biagini Myers, T.L. Patterson, et al. 2012. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS One 7 (4): e33454.CrossRefGoogle Scholar
  18. 18.
    Winter, J., S. Jung, S. Keller, R.I. Gregory, and S. Diederichs. 2009. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature Cell Biology 11 (3): 228–234.CrossRefGoogle Scholar
  19. 19.
    Lu, T.X., and M.E. Rothenberg. 2013. Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. The Journal of Allergy and Clinical Immunology 132 (1): 3–13 quiz 4.CrossRefGoogle Scholar
  20. 20.
    Pichavant M, Goya S, Hamelmann E, Gelfand EW, Umetsu DT. Animal models of airway sensitization. Current Protocols in Immunology. 2007;Chapter 15:Unit 15 8.Google Scholar
  21. 21.
    McGeachie, M.J., J.S. Davis, A.T. Kho, A. Dahlin, J.E. Sordillo, M. Sun, et al. 2017. Asthma remission: predicting future airways responsiveness using an miRNA network. The Journal of Allergy and Clinical Immunology 140 (2): 598–600 e8.CrossRefGoogle Scholar
  22. 22.
    Croset, M., F. Pantano, C.W.S. Kan, E. Bonnelye, F. Descotes, C. Alix-Panabieres, et al. 2018. miRNA-30 family members inhibit breast cancer invasion, osteomimicry, and bone destruction by directly targeting multiple bone metastasis-associated genes. Cancer Research 78 (18): 5259–5273.CrossRefGoogle Scholar
  23. 23.
    Singh, A.K., R.K. Pandey, C. Shaha, and R. Madhubala. 2016. MicroRNA expression profiling of Leishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy. Autophagy 12 (10): 1817–1831.CrossRefGoogle Scholar
  24. 24.
    Xu, J., Y. Wang, X. Tan, and H. Jing. 2012. MicroRNAs in autophagy and their emerging roles in crosstalk with apoptosis. Autophagy 8 (6): 873–882.CrossRefGoogle Scholar
  25. 25.
    Taby, R., and J.P. Issa. 2010. Cancer epigenetics. CA: a Cancer Journal for Clinicians 60 (6): 376–392.Google Scholar
  26. 26.
    Hu, R., D.A. Kagele, T.B. Huffaker, M.C. Runtsch, M. Alexander, J. Liu, E. Bake, W. Su, M.A. Williams, D.S. Rao, T. Möller, G.A. Garden, J.L. Round, and R.M. O’Connell. 2014. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity. 41 (4): 605–619.CrossRefGoogle Scholar
  27. 27.
    Xie, Z., and D.J. Klionsky. 2007. Autophagosome formation: core machinery and adaptations. Nature Cell Biology 9 (10): 1102–1109.CrossRefGoogle Scholar
  28. 28.
    Ye, X., X.J. Zhou, and H. Zhang. 2018. Exploring the role of autophagy-related gene 5 (ATG5) yields important insights into autophagy in autoimmune/autoinflammatory diseases. Frontiers in Immunology 9: 2334.CrossRefGoogle Scholar
  29. 29.
    Ni, H.M., B.L. Woolbright, J. Williams, B. Copple, W. Cui, J.P. Luyendyk, H. Jaeschke, and W.X. Ding. 2014. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. Journal of Hepatology 61 (3): 617–625.CrossRefGoogle Scholar
  30. 30.
    Poon, A.H., D.F. Choy, F. Chouiali, R.K. Ramakrishnan, B. Mahboub, S. Audusseau, et al. 2017. Increased autophagy-related 5 gene expression is associated with collagen expression in the airways of refractory asthmatics. Frontiers in Immunology 8: 355.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PaediatricsTiantai County People’s HospitalTaizhou CityChina
  2. 2.Department of MedicineThe Children’s Hospital of HangzhouHangzhouChina

Personalised recommendations

Cite article

Buy options