, Volume 42, Issue 2, pp 548–558 | Cite as

Gasdermin-d Played a Critical Role in the Cyclic Stretch–Induced Inflammatory Reaction in Human Periodontal Ligament Cells

  • Jiabao Zhuang
  • Yingying Wang
  • Fang Qu
  • Yaqin Wu
  • Dan Zhao
  • Chun XuEmail author


It has been shown that cyclic stretch could induce inflammatory response such as pyroptosis and the release of IL-1β in human periodontal ligament cells, through activating inflammasome and related caspases. Though gasdermin-d (GSDMD) has been reported to be present in some inflammatory diseases and function as a crucial executioner of pyroptosis, the role of GSDMD in the stretch-induced inflammatory response in human periodontal ligament cells (HPDLCs) has not been well clarified. In this study, it was found that GSDMD was activated by cyclic stretch, and its activation affected the pyroptotic rate in HPDLCs, leading to the maturation and secretion of IL-1β and IL-18 ultimately. In addition, GSDMD was found to be regulated by caspase-1 directly. Nevertheless, the exact relationship between inflammasomes and GSDMD in the stretch-induced inflammatory response still needs to be further elucidated.


cyclic stretch human periodontal ligament cells gasdermin-d inflammation 



This work was supported by National Natural Science Foundation of China (grant numbers 31470903, 31270991, 30900282), Shanghai Summit & Plateau Disciplines, Shanghai Pujiang Program (grant number 13PJD021), Science and Technology Commission of Shanghai (grant number 10QA1404200, 08411961500, 07ZR14070), and Shanghai Leading Academic Discipline Project (grant numbers S30206-sms02, T0202).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Statement

The experimental protocol was reviewed and approved by the Ethics Committee of Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine. The relevant judgment’s reference number is [2017]96.


  1. 1.
    McCulloch, C.A., P. Lekic, and M.D. McKee. 2000. Role of physical forces in regulating the form and function of the periodontal ligament. Periodontol 2000 (24): 56–72.CrossRefGoogle Scholar
  2. 2.
    Kim, J.H., M.S. Kang, M. Eltohamy, T.H. Kim, and H.W. Kim. 2016. Dynamic mechanical and nanofibrous topological combinatory cues designed for periodontal ligament engineering. PLoS One 11 (3): e0149967.CrossRefGoogle Scholar
  3. 3.
    Matsuda, N., K. Yokoyama, S. Takeshita, and M. Watanabe. 1998. Role of epidermal growth factor and its receptor in mechanical stress-induced differentiation of human periodontal ligament cells in vitro. Archives of Oral Biology 43 (12): 987–997.CrossRefGoogle Scholar
  4. 4.
    Yang, Y., F.M.V. Rossi, and E.E. Putnins. 2010. Periodontal regeneration using engineered bone marrow mesenchymal stromal cells. Biomaterials 31: 8574–8582.CrossRefGoogle Scholar
  5. 5.
    Kaneko, S., K. Ohashi, K. Soma, and M. Yanagishita. 2001. Occlusal hypofunction causes changes of proteoglycan content in the rat periodontal ligament. Journal of Periodontal Research 36 (1): 9–17.CrossRefGoogle Scholar
  6. 6.
    Kaku, M., K. Uoshima, Y. Yamashita, and H. Miura. 2005. Investigation of periodontal ligament reaction upon excessive occlusal load—osteopontin induction among periodontal ligament cells. Journal of Periodontal Research 40 (1): 59–66.CrossRefGoogle Scholar
  7. 7.
    Jin, L.J., and C.F. Cao. 1992. Clinical diagnosis of trauma from occlusion and its relation with severity of periodontitis. Journal of Clinical Periodontology 19 (2): 92–97.CrossRefGoogle Scholar
  8. 8.
    Harrel, S.K. 2003. Occlusal forces as a risk factor for periodontal disease. Periodontol 2000 (32): 111–117.CrossRefGoogle Scholar
  9. 9.
    Feller, L., R.A. Khammissa, I. Schechter, G. Thomadakis, J. Fourie, and J. Lemmer. 2015. Biological events periodontal ligament and alveolar bone associated with application of orthodontic forces. ScientificWorldJournal 2015: 876509.Google Scholar
  10. 10.
    Chowdhury, B., A.L. David, C. Thrasivoulou, D.L. Becker, D.L. Bader, and T.T. Chowdhury. 2014. Tense strain increased COX-2 expression and PGE2 release leading to weaking of the human amniotic membrane. Placenta 35: 1057–1064.CrossRefGoogle Scholar
  11. 11.
    Karadottir, H., N.N. Kulkarni, T. Gudjonsson, S. Karason, and G.H. Gudmundsson. 2015. Cyclic stretch down-regulates cathelicidin antimicrobial peptide expression and activates a pro-inflammatory response in human bronchial epithelial cells. PeerJ 3: 31483.CrossRefGoogle Scholar
  12. 12.
    Lin, Y.M., F. Li, and X.Z. Shi. 2014. Mechanical stress is a pro-inflammatory stimulus in the gut: in vitro, in vivo and ex vivo evidence. PLoS One 9: e106242.CrossRefGoogle Scholar
  13. 13.
    Jacobs, C., C. Walter, T. Ziebart, S. Grimm, D. Meila, E. Krieger, and H. Wehtbein. 2014. Induction of IL-6 and MMP-8 in human periodontal fibroblasts by static tensile strain. Clinical Oral Investigations 18: 901–908.CrossRefGoogle Scholar
  14. 14.
    Bletsa, A., E. Berggreen, and P. Brudvik. 2006. Interleukin-1 alpha and tumor necrosis factor-alpha expression during the early phases of orthodontic tooth movement in rats. European Journal of Oral Sciences 114: 423–429.CrossRefGoogle Scholar
  15. 15.
    Maeda, A., K. Soejima, K. Bandow, K. Kuroe, K. Kakimoto, S. Miyawaki, A. Okamoto, and T. Matsuguchi. 2007. Force-induced IL-8 from periodontal ligament cells requires IL-1beta. Journal of Dental Research 86: 629–634.CrossRefGoogle Scholar
  16. 16.
    Ren, Y., and A. Vissink. 2008. Cytokines in crevicular fluid and orthodontic tooth movement. European Journal of Oral Sciences 116: 89–97.CrossRefGoogle Scholar
  17. 17.
    Uematsu, S., M. Mogi, and T. Deguchi. 1996. Interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth factor, and beta 2-microglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth movement. Journal of Dental Research 75: 562–567.CrossRefGoogle Scholar
  18. 18.
    Zhao, D., Y. Wu, J. Zhuang, C. Xu, and F. Zhang. 2016. Activation of NLRP1 and NLRP3 inflammasomes contributed to cyclic stretch-induced pyroptosis and release of IL-1β in human periodontal ligament cells. Oncotarget 7 (42): 292–302.CrossRefGoogle Scholar
  19. 19.
    Schroder, K., and J. Tshopp. 2010. The inflammasomes. Cell 140: 821–832.CrossRefGoogle Scholar
  20. 20.
    Van de veerdonk, F.L., M.G. Netea, C.A. Dinarello, and L.A. Joosten. 2011. Inflammasome activation of IL-1beta and IL-18 processing during infection. Trends in Immunology 32: 110–116.CrossRefGoogle Scholar
  21. 21.
    Cookson, B.T., and M.A. Brennan. 2001. Pro-inflammatory programmed cell death. Trends Microbial. 9: 113–114.CrossRefGoogle Scholar
  22. 22.
    Kuipers, M.T., H. Aslami, J.R. Janczy, K.F. van der Sluijs, A.P. Vlaar, E.K. Wolthuis, G. Choi, J.J. Roelofs, R.A. Flavell, F.S. Sutterwala, P. Bresser, J.C. Leemans, T. van der Poll, M.J. Schultz, and C.W. Wieland. 2012. Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. Anesthesiology 116: 1104–1115.CrossRefGoogle Scholar
  23. 23.
    Taabazuing, C.Y., M.C. Okondo, and D.A. Bachovchin. 2017. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chemical Biology 24 (4): 507–514.CrossRefGoogle Scholar
  24. 24.
    de Vasconcelos, N.M., N. Van Opdenbosch, H. Van Gorp, E. Parthoens, and M. Lamkanfi. 2018. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death and Differentiation.
  25. 25.
    Aglietti, R.A., A. Estevez, A. Gupta, M.G. Ramirez, P.S. Liu, N. Kayagaki, C. Ciferri, V.M. Dixit, and E.C. Dueber. 2016. GSDMD p30 elicited by caspase-11 during pyroptosis forms pores in membrane. Proceedings of the National Academy of Sciences of the United States of America 113: 7858–7863.CrossRefGoogle Scholar
  26. 26.
    Chen, X., W.T. He, L. Hu, J. Li, Y. Fang, X. Wang, X. Xu, Z. Wang, K. Huang, and J. Han. 2016. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Research 26: 1007–1020.CrossRefGoogle Scholar
  27. 27.
    Ding, J., K. Wang, W. Liu, Y. She, Q. Sun, J. Shi, H. Sun, D.C. Wang, and F. Shao. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535: 111–116.CrossRefGoogle Scholar
  28. 28.
    He, W.T., H. Wan, L. Hu, P. Chen, X. Wang, Z. Huang, Z.H. Yang, C.Q. Zhong, and J. Han. 2015. Gasdermin D is an executor of pyroptosis and required for interlrukin-1β secretion. Cell Research 25: 1285–1298.CrossRefGoogle Scholar
  29. 29.
    Yamaguchi, M., N. Shimizu, Y. Shibata, and Y. Abiko. 1996. Effects of different magnitudes of tension-force on alkaline phosphatase activity in periodontal ligament cells. Journal of Dental Research 75 (3): 889–894.CrossRefGoogle Scholar
  30. 30.
    Zhong, W., C. Xu, F. Zhang, X. Zhang, X. Jiang, and D. Ye. 2008. Cyclic stretching force-induced early apoptosis in human periodontal ligament cells. Oral Diseases 14 (3): 270–276.CrossRefGoogle Scholar
  31. 31.
    Hao, Y., C. Xu, S. Sun, and F. Zhang. 2009. Cyclic stretching force induces apoptosis in human periodontal ligament cells via caspase-9. Archives of Oral Biology 54 (9): 864–870.CrossRefGoogle Scholar
  32. 32.
    Agarwal, S., P. Long, A. Seyedain, N. Piesco, A. Shree, and R. Gassner. 2003. A central role for the nuclear factor-kappaB pathway in anti-inflammatory and proinflammatory actions of mechanical strain. The FASEB Journal 17 (8): 899–901.CrossRefGoogle Scholar
  33. 33.
    Nokhbehsaim, M., B. Deschner, J. Winter, S. Reimann, C. Bourauel, S. Jepsen, A. Jager, and J. Deschner. 2010. Contribution of orthodontic load to inflammation-mediated periodontal destruction. Journal of Orofacial Orthopedics 71 (6): 390–402.CrossRefGoogle Scholar
  34. 34.
    Ma, J., D. Zhao, Y. Wu, C. Xu, and F. Zhang. 2015. Cyclic stretch induced gene expression of extracellular matrix and adhesion molecules in human periodontal ligament cells. Archives of Oral Biology 60 (3): 447–455.CrossRefGoogle Scholar
  35. 35.
    Glickman, I., and J.B. Smalow. 1962. Alteration in the pathway of gingival inflammation into the underlying tissues induced by excessive occlusal forces. Journal of Periodontology 33: 7–13.Google Scholar
  36. 36.
    Biancu, S., I. Ericsson, and J. Lindhe. 1995. Periodontal ligament tissue reactions to trauma and gingival inflammation. An experimental study in the beagle dog. J Clin Periodontol 22: 772–779.CrossRefGoogle Scholar
  37. 37.
    Bostanci, N., G. Emingil, B. Saygan, O. Turkoglu, G. Atilla, M.A. Curtis, and G.N. Belibasakis. 2009. Expression and regulation of the NALP3 inflammasome complex in periodontal diseases. Clinical and Experimental Immunology 157: 415–422.CrossRefGoogle Scholar
  38. 38.
    Liu, W., J. Liu, W. Wang, Y. Wang, and X. Ouyang. 2018. NLRP6 induces pyroptosis by activation of caspase-1 in gingival fibroblasts. Journal of Dental Research.
  39. 39.
    Sauer, J.D., C.E. Witte, J. Zemansky, B. Hanson, P. Lauer, and D.A. Portnoy. 2010. Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host & Microbe 7 (5): 412–419.CrossRefGoogle Scholar
  40. 40.
    Cheng, R., Y. Feng, R. Zhang, W. Liu, L. Lei, and T. Hu. 2018. The extent of pyroptosis varies in different stages of apical periodontitis. Biochimica et Biophysica Acta 1864 (1): 226–237.CrossRefGoogle Scholar
  41. 41.
    Kayagaki, N., I.B. Stowe, B.L. Lee, K. O’Rourke, K. Anderson, S. Warming, T. Cuellar, B. Haley, M. Roose-Girma, Q.T. Phung, P.S. Liu, J.R. Lill, H. Li, J. Wu, S. Kummerfeld, J. Zhang, W.P. Lee, S.J. Snipas, G.S. Salvesen, L.X. Morris, L. Fitzgerald, Y. Zhang, E.M. Bertram, C.C. Goodnow, and V.M. Dixit. 2015. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. Nature 526: 666–671.CrossRefGoogle Scholar
  42. 42.
    Shi, J., Y. Zhao, K. Wang, X. Shi, Y. Wang, H. Huang, Y. Zhuang, T. Cai, F. Wang, and F. Shao. 2016. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. The EMBO Journal 35: 1766–1778.CrossRefGoogle Scholar
  43. 43.
    Mulvihill, E., L. Sborgi, S.A. Mari, M. Pfreundschuh, S. Hiller, and D.J. Muller. 2018. Mechanism of membrane pore formation by human gasdermin-D. EMBO J: e98321.Google Scholar
  44. 44.
    Kanneganti, A., R.K.S. Malireddi, P.H.V. Saavedra, L. Vande Walle, H. Van Gorp, H. Kambara, H. Tillman, P. Vogel, H.R. Luo, R.J. Xavier, H. Chi, and M. Lamkanfi. 2018. GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. The Journal of Experimental Medicine 215 (6): 1519–1529.CrossRefGoogle Scholar
  45. 45.
    Gao, Y.L., J.H. Zhai, and Y.F. Chai. 2018. Recent advances in the molecular mechanisms underlying pyroptosis in sepsis. Mediators of Inflammation: 5828823.Google Scholar
  46. 46.
    McKenzie, B.A., M.K. Mamik, L.B. Saito, R. Boghozian, M.C. Monaco, E.O. Major, J.Q. Lu, W.G. Branton, and C. Power. 2018. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. 115 (26): E6065–E6074.Google Scholar
  47. 47.
    Liu, X., and J. Lieberman. 2017. A mechanistic understanding of pyroptosis: the fiery death triggered by invasive infection. Advances in Immunology 135: 81–117.CrossRefGoogle Scholar
  48. 48.
    Sborgi, L., S. Ruhl, E. Mulvihill, J. Pipercevic, R. Heilig, H. Stahlberg, C.J. Farady, D.J. Muller, P. Broz, and S. Hiller. 2016. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. The EMBO Journal 35 (16): 1766–1778.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jiabao Zhuang
    • 1
    • 2
    • 3
  • Yingying Wang
    • 1
    • 2
    • 3
  • Fang Qu
    • 1
    • 2
    • 3
  • Yaqin Wu
    • 1
    • 2
    • 3
  • Dan Zhao
    • 1
    • 2
    • 3
  • Chun Xu
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Prosthodontics, Shanghai Ninth People’s Hospital, College of StomatologyShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.National Clinical Research Center for Oral DiseasesShanghaiChina
  3. 3.Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of StomatologyShanghaiChina

Personalised recommendations