Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Holgate, S.T. 2008. The airway epithelium is central to the pathogenesis of asthma. Allergology International 57 (1): 1–10.

    Article  CAS  Google Scholar 

  2. Holgate, S.T. 2008. Pathogenesis of asthma. Clinical and Experimental Allergy 38 (6): 872–897.

    Article  CAS  Google Scholar 

  3. Poe, C.A., and S. Johnson. 1972. Psychologists’ conception of optimal adjustment. Journal of Clinical Psychology 28 (4): 449–451.

    Article  CAS  Google Scholar 

  4. Papi, A., C. Brightling, S.E. Pedersen, and H.K. Reddel. 2018. Asthma. Lancet. 391 (10122): 783–800.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  10. Malaviya, R., J.D. Laskin, and D.L. Laskin. 2017. Anti-TNF alpha therapy in inflammatory lung diseases. Pharmacology & Therapeutics 180: 90–98.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  25. Taby, R., and J.P. Issa. 2010. Cancer epigenetics. CA: a Cancer Journal for Clinicians 60 (6): 376–392.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

  27. Xie, Z., and D.J. Klionsky. 2007. Autophagosome formation: core machinery and adaptations. Nature Cell Biology 9 (10): 1102–1109.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Paediatrics, Tiantai County People’s Hospital, 1 Kang ling Road, Tiantai County, Taizhou City, Zhejiang, China

    Bin Bin Li & Fuzhen Pang

  2. Department of Medicine, The Children’s Hospital of Hangzhou, 196 Wen Hui Road, Hangzhou, 310014, China

    Yun long Chen

Authors
  1. Bin Bin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun long Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fuzhen Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yun long Chen or Fuzhen Pang.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, B.B., Chen, Y.l. & Pang, F. MicroRNA-30a Targets ATG5 and Attenuates Airway Fibrosis in Asthma by Suppressing Autophagy. Inflammation 43, 44–53 (2020). https://doi.org/10.1007/s10753-019-01076-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01076-0

KEY WORDS

Search

Navigation