Skip to main content

Advertisement

SpringerLink
Log in

Collagen Triple Helix Repeat Containing 1 Deficiency Protects Against Airway Remodeling and Inflammation in Asthma Models In Vivo and In Vitro

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Asthma is a chronic inflammatory disease characterized by airway remodeling and lung inflammation. Collagen triple helix repeat containing 1 (CTHRC1), a glycoprotein, is involved in multiple pathological processes, including inflammation and fibrosis. However, the function of CTHRC1 in asthma remains unclear. In the present study, the mouse asthma model was successfully generated by sensitizing and challenging mice with ovalbumin (OVA). CTHRC1 expression at both RNA and protein levels was significantly upregulated in lung tissues of asthmatic mice. Asthmatic mice exhibited significant airway remodeling as evidenced by increased bronchial wall and smooth muscle cell layer thickness, goblet cell hyperplasia and collagen deposition, and epithelial-mesenchymal transition (EMT), but those characteristics were reversed by CTHRC1 silencing. The cell model with transforming growth factor-β1 (TGF-β1) induction in bronchial epithelial cells (BEAS-2B) was conducted to verify the effects of CTHRC1 on EMT, a classic mechanism that mediates airway remodeling. The results showed that TGF-β1 stimulation increased CTHRC1 expression, and CTHRC1 knockdown inhibited TGF-β1-induced EMT. OVA-treated mice also showed increased inflammatory cell infiltration and the production of OVA-specific immunoglobulin E (IgE), interleukin (IL)-4, IL-5, and IL-13, which were decreased by CTHRC1 downregulation. The effects of CTHRC1 on OVA-induced airway inflammation were further determined by treating BEAS-2B cells with IL-13, in which CTHRC1 knockdown reduced the IL-13-induced secretion of pro-inflammatory factors, including IL-4 and IL-5. In conclusion, these results indicate that CTHRC1 silencing attenuates asthmatic airway remodeling and inflammation in vivo and in vitro, suggesting that CTHRC1 may be a potential target for asthma treatment.

Graphical Abstract

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
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data used or analyzed during the current study are available from the corresponding author upon reasonable request.

References

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

    Article  PubMed  Google Scholar 

  2. Holgate, S.T., S. Wenzel, D.S. Postma, S.T. Weiss, H. Renz, and P.D. Sly. 2015. Asthma. Nature Reviews Disease Primers 1: 15025.

    Article  PubMed  Google Scholar 

  3. Wang, K.C.W., G.M. Donovan, A.L. James, and P.B. Noble. 2020. Asthma: Pharmacological degradation of the airway smooth muscle layer. The International Journal of Biochemistry & Cell Biology 126: 105818.

    Article  CAS  Google Scholar 

  4. Finotto, S. 2019. Resolution of allergic asthma. Seminars In Immunopathology 41: 665–674.

    Article  PubMed  Google Scholar 

  5. Morimoto, Y., K. Hirahara, M. Kiuchi, T. Wada, T. Ichikawa, T. Kanno, M. Okano, K. Kokubo, A. Onodera, D. Sakurai, Y. Okamoto, and T. Nakayama. 2018. Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis. Immunity 49: 134-150.e6.

    Article  CAS  PubMed  Google Scholar 

  6. Hough, K.P., M.L. Curtiss, T.J. Blain, R.-M. Liu, J. Trevor, J.S. Deshane, and V.J. Thannickal. 2020. Airway remodeling in asthma. Frontiers In Medicine 7: 191.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lambrecht, B.N., and H. Hammad. 2015. The immunology of asthma. Nature immunology 16: 45–56.

    Article  CAS  PubMed  Google Scholar 

  8. Sun, Z., N. Ji, Q. Ma, R. Zhu, Z. Chen, Z. Wang, Y. Qian, C. Wu, F. Hu, M. Huang, and M. Zhang. 2020. Epithelial-mesenchymal transition in asthma airway remodeling is regulated by the IL-33/CD146 axis. Frontiers In Immunology 11: 1598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Riemma, M.A., I. Cerqua, B. Romano, E. Irollo, A. Bertolino, R. Camerlingo, E. Granato, G. Rea, S. Scala, M. Terlizzi, G. Spaziano, R. Sorrentino, B. D’Agostino, F. Roviezzo, and G. Cirino. 2022. Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease. British Journal of Pharmacology 179: 1753–1768.

    Article  CAS  PubMed  Google Scholar 

  10. Guo, Y., C. Jiang, S. Yao, L. Ma, H. Zhang, X. Wang, S. Xu, and Z. Cao. 2021. CTHRC1 knockdown promotes inflammatory responses partially by p38 MAPK activation in human periodontal ligament cells. Inflammation 44: 1831–1842.

    Article  CAS  PubMed  Google Scholar 

  11. Tsukui, T., K.H. Sun, J.B. Wetter, J.R. Wilson-Kanamori, L.A. Hazelwood, and N.C. Henderson. 2020. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nature Communications 11: 1920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jin, X.-F., H. Li, S. Zong, and H.-Y. Li. 2016. Knockdown of collagen triple helix repeat containing-1 inhibits the proliferation and epithelial-to-mesenchymal transition in renal cell carcinoma cells. Oncology Research 24: 477–485.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang, C., Z. Li, F. Shao, X. Yang, X. Feng, S. Shi, Y. Gao, and J. He. 2017. High expression of collagen triple helix repeat containing 1 (CTHRC1) facilitates progression of oesophageal squamous cell carcinoma through MAPK/MEK/ERK/FRA-1 activation. Journal of Experimental Clinical Cancer Research 36: 84.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jiang, N., Y. Cui, J. Liu, X. Zhu, H. Wu, Z. Yang, and Z. Ke. 2016. Multidimensional roles of collagen triple helix repeat containing 1 (CTHRC1) in malignant cancers. Journal of Cancer 7: 2213–2220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mei, D., Y. Zhu, L. Zhang, and W. Wei. 2020. The role of CTHRC1 in regulation of multiple signaling and tumor progression and metastasis. Mediators of Inflammation 2020: 9578701.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tsukui, T., K.-H. Sun, J.B. Wetter, J.R. Wilson-Kanamori, L.A. Hazelwood, N.C. Henderson, T.S. Adams, J.C. Schupp, S.D. Poli, I.O. Rosas, N. Kaminski, M.A. Matthay, P.J. Wolters, and D. Sheppard. 2020. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nature Communications 11: 1920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. LeClair, R.J., T. Durmus, Q. Wang, P. Pyagay, A. Terzic, and V. Lindner. 2007. Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation. Circulation research 100: 826–833.

    Article  CAS  PubMed  Google Scholar 

  18. Li, J., Y. Wang, M. Ma, S. Jiang, X. Zhang, Y. Zhang, X. Yang, C. Xu, G. Tian, Q. Li, Y. Wang, L. Zhu, H. Nie, M. Feng, Q. Xia, J. Gu, Q. Xu, and Z. Zhang. 2019. Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling. eBioMedicine 40: 43–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Myngbay, A., and L. Manarbek. 2021. The role of collagen triple helix repeat-containing 1 protein (CTHRC1) in rheumatoid arthritis. International Journal of Molecular Sciences 22: 2426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smith, L.C., S. Moreno, L. Robertson, S. Robinson, K. Gant, A.J. Bryant, and T. Sabo-Attwood. 2018. Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respiratory Research 19: 160.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ni, S., F. Ren, M. Xu, C. Tan, W. Weng, Z. Huang, W. Sheng, and D. Huang. 2018. CTHRC1 overexpression predicts poor survival and enhances epithelial-mesenchymal transition in colorectal cancer. Cancer Medicine 7: 5643–5654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tai, Y., Y. Zhu, D. Mei, H. Wang, Q. Yu, C. Hong, X. Cai, L. Xu, J. Ge, F. Liang, C. Jiang, Z. Xue, L. Hu, R. Liu, T. Zhang, P. Wang, X. Zhang, F. Zhang, W. Wei, and L. Zhang. 2021. IgD promotes pannus formation by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in FLS of CIA rats and the regulation of IgD-Fc-Ig fusion protein. International immunopharmacology 101: 108261.

    Article  CAS  PubMed  Google Scholar 

  23. Jin, Y.R., J.P. Stohn, Q. Wang, K. Nagano, R. Baron, M.L. Bouxsein, C.J. Rosen, V.A. Adarichev, and V. Lindner. 2017. Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1. Bone 97: 153–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Myngbay, A., Y. Bexeitov, A. Adilbayeva, Z. Assylbekov, B.P. Yevstratenko, R.M. Aitzhanova, B. Matkarimov, V.A. Adarichev, and J. Kunz. 2019. CTHRC1: A new candidate biomarker for improved rheumatoid arthritis diagnosis. Frontiers In Immunology 10: 1353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Myou, S., A.R. Leff, S. Myo, E. Boetticher, J. Tong, A.Y. Meliton, J. Liu, N.M. Munoz, and X. Zhu. 2003. Blockade of inflammation and airway hyperresponsiveness in immune-sensitized mice by dominant-negative phosphoinositide 3-kinase-TAT. The Journal of Experimental Medicine 198: 1573–1582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pu, Y., Y. Liu, S. Liao, S. Miao, L. Zhou, and L. Wan. 2018. Azithromycin ameliorates OVA-induced airway remodeling in Balb/c mice via suppression of epithelial-to-mesenchymal transition. International Immunopharmacology 58: 87–93.

    Article  CAS  PubMed  Google Scholar 

  27. Wu, L.Q., R.L. Wang, Y.R. Dai, F.Q. Li, H.Y. Wu, S.S. Yan, L.R. Wang, L.D. Jin, and X.D. Xia. 2015. Roxithromycin suppresses airway remodeling and modulates the expression of caveolin-1 and phospho-p42/p44MAPK in asthmatic rats. International immunopharmacology 24: 247–255.

    Article  CAS  PubMed  Google Scholar 

  28. Loh, C.-Y., J.Y. Chai, T.F. Tang, W.F. Wong, G. Sethi, M.K. Shanmugam, P.P. Chong, and C.Y. Looi. 2019. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: Signaling, therapeutic implications, and challenges. Cells 8: 1118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee, H.-W., C.C. Jose, and S. Cuddapah. 2021. Epithelial-mesenchymal transition: Insights into nickel-induced lung diseases. Seminars In Cancer Biology 76: 99–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Banno, A., A.T. Reddy, S.P. Lakshmi, and R.C. Reddy. 2020. Bidirectional interaction of airway epithelial remodeling and inflammation in asthma. Clinical Science 134: 1063–1079.

    Article  CAS  PubMed  Google Scholar 

  31. Gubernatorova, E.O., O.A. Namakanova, A.V. Tumanov, M.S. Drutskaya, and S.A. Nedospasov. 2019. Mouse models of severe asthma for evaluation of therapeutic cytokine targeting. Immunology Letters 207: 73–83.

    Article  CAS  PubMed  Google Scholar 

  32. Bates, J.H.T., M. Rincon, and C.G. Irvin. 2009. Animal models of asthma. American Journal of Physiology. Lung Cellular and Molecular Physiology 297: L401–L410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Komi, Elieh Ali, and D. and L. Bjermer. 2019. Mast cell-mediated orchestration of the immune responses in human allergic asthma: Current insights. Clinical Reviews in Allergy & Immunology 56: 234–247.

    Article  Google Scholar 

  34. Jia, A., Y. Wang, W. Sun, B. Xiao, L. Mu, Y. Wei, L. Xu, C. Peng, D. Zhang, H. Shen, and X. Xiang. 2017. Comparison of the roles of house dust mite allergens, ovalbumin and lipopolysaccharides in the sensitization of mice to establish a model of severe neutrophilic asthma. Experimental and Therapeutic Medicine 14: 2126–2134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, Y., L. Wei, C. He, R. Chen, and L. Meng. 2021. Lipoxin A4 inhibits ovalbumin-induced airway inflammation and airway remodeling in a mouse model of asthma. Chemico-biological Interactions 349: 109660.

    Article  CAS  PubMed  Google Scholar 

  36. Al-Muhsen, S., J.R. Johnson, and Q. Hamid. 2011. Remodeling in asthma. The Journal of Allergy and Clinical Immunology 128: 451–462.

    Article  PubMed  Google Scholar 

  37. Jin, J., and S. Togo. 2019. Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1. Respiratory Research 20: 119.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bian, Z., Q. Miao, W. Zhong, H. Zhang, Q. Wang, Y. Peng, X. Chen, C. Guo, L. Shen, F. Yang, J. Xu, D. Qiu, J. Fang, S. Friedman, R. Tang, M.E. Gershwin, and X. Ma. 2015. Treatment of cholestatic fibrosis by altering gene expression of Cthrc1: Implications for autoimmune and non-autoimmune liver disease. Journal of Autoimmunity 63: 76–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shen, Z., T. Su, J. Chen, Z. Xie, and J. Li. 2021. Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models. Annals of Translational Medicine 9: 801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pain, M., O. Bermudez, P. Lacoste, P.J. Royer, K. Botturi, A. Tissot, S. Brouard, O. Eickelberg, and A. Magnan. 2014. Tissue remodelling in chronic bronchial diseases: From the epithelial to mesenchymal phenotype. European Respiratory Review 23: 118–130.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yang, Z.C., Z.H. Qu, M.J. Yi, Y.C. Shan, N. Ran, L. Xu, and X.J. Liu. 2019. MiR-448-5p inhibits TGF-β1-induced epithelial-mesenchymal transition and pulmonary fibrosis by targeting Six1 in asthma. Journal of cellular physiology 234: 8804–8814.

    Article  CAS  PubMed  Google Scholar 

  42. Fan, Q., and Y. Jian. 2020. MiR-203a-3p regulates TGF-β1-induced epithelial-mesenchymal transition (EMT) in asthma by regulating Smad3 pathway through SIX1. Bioscience reports 40: BSR20192645.

  43. Serrano-Gomez, S.J., M. Maziveyi, and S.K. Alahari. 2016. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Molecular Cancer 15: 18.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Liu, J., W. Li, S. Liu, X. Zheng, L. Shi, W. Zhang, and H. Yang. 2017. Knockdown of collagen triple helix repeat containing 1 (CTHRC1) inhibits epithelial-mesenchymal transition and cellular migration in glioblastoma cells. Oncology Research 25: 225–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mostaço-Guidolin, L.B., E.T. Osei, J. Ullah, S. Hajimohammadi, M. Fouadi, X. Li, V. Li, F. Shaheen, C.X. Yang, F. Chu, D.J. Cole, C.A. Brandsma, I.H. Heijink, G.N. Maksym, D. Walker, and T.L. Hackett. 2019. Defective fibrillar collagen organization by fibroblasts contributes to airway remodeling in asthma. American Journal of Respiratory and Critical Care Medicine 200: 431–443.

    Article  PubMed  Google Scholar 

  46. Boonpiyathad, T., Z.C. Sözener, P. Satitsuksanoa, and C.A. Akdis. 2019. Immunologic mechanisms in asthma. Seminars In Immunology 46: 101333.

    Article  CAS  PubMed  Google Scholar 

  47. Lambrecht, B.N., H. Hammad, and J.V. Fahy. 2019. The cytokines of asthma. Immunity 50: 975–991.

    Article  CAS  PubMed  Google Scholar 

  48. Hammad, H., and B.N. Lambrecht. 2021. The basic immunology of asthma. Cell 184: 1469–1485.

    Article  CAS  PubMed  Google Scholar 

  49. Seibold, M.A. 2018. Interleukin-13 stimulation reveals the cellular and functional plasticity of the airway epithelium. Annals of the American Thoracic Society 15: S98–S102.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tay, H.L., and P.S. Foster. 2020. Biologics or immunotherapeutics for asthma? Pharmacological Research 158: 104782.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Liaoning Province, 110004, China

    Yong Feng, Jiapeng Hu, Fen Liu & Yunxiao Shang

Authors
  1. Yong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiapeng Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunxiao Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yunxiao Shang.

Ethics declarations

Ethics Approval

All animal experiments were approved by the Ethics Committee of the Shengjing Hospital of China Medical University (No. 2019PS536K).

Consent to Participate

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, Y., Hu, J., Liu, F. et al. Collagen Triple Helix Repeat Containing 1 Deficiency Protects Against Airway Remodeling and Inflammation in Asthma Models In Vivo and In Vitro. Inflammation 46, 925–940 (2023). https://doi.org/10.1007/s10753-022-01781-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-022-01781-3

KEY WORDS

Search

Navigation