Advertisement

Inflammation

, Volume 41, Issue 5, pp 1852–1863 | Cite as

Progranulin Is Positively Associated with Intervertebral Disc Degeneration by Interaction with IL-10 and IL-17 Through TNF Pathways

  • Shaoyi Wang
  • Jianlu Wei
  • Yuchen Fan
  • Hong Ding
  • Huichao Tian
  • Xiaocong Zhou
  • Lei ChengEmail author
ORIGINAL ARTICLE

Abstract

Progranulin (PGRN) is a widely expressed growth factor that effectively inhibits tumor necrosis factor α (TNFα)-mediated inflammatory response. TNFα is involved in intervertebral disc degeneration (IDD) and plays a key role. This study aims to determine the role of PGRN in the intervertebral disc degeneration process. We collected intervertebral discs (IVDs) from humans and mice with different genetic backgrounds. We examined the expression of PGRN in IVD tissues by immunohistochemistry staining and Western blotting assay. We examined the peripheral serum level of PGRN by ELISA assay. Murine IVD tissue samples were taken to undergo safranin O, HE, and immunohistochemistry staining. Primary human nucleus pulposus cells were used for ELISA and RT-PCR assays. PGRN as well as interlukin-10 (IL-10) and interlukin-17 (IL-17) expressions were elevated in degenerative discs and peripheral blood sera. Loss of PGRN led to accelerated disc degeneration in the animal model, along with decreased expression of IL-10 and increased expression of IL-17. Additionally, the PGRN level was positively related to levels of IL-10 and IL-17. In vitro study suggested that PGRN protected against disc degeneration by inducing IL-10 and reducing IL-17. PGRN is associated with intervertebral disc degeneration through interfering with IL-10 and IL-17; thus, PGRN could be an interesting biomarker for diagnosis and a potential treatment target.

KEY WORDS

progranulin TNFα intervertebral disc degeneration IL-10 IL-17 

Abbreviations

IL-1β

interleukin-1β

IVD

intervertebral disk

MMP13

matrix metallopeptidase 13

PGRN

progranulin

TNF-α

tumor necrosis factor α

Notes

Acknowledgments

The study was supported by grants from the National Natural Science Foundation of China (81572191).

Author Contributions

Study concept and design: Lei Cheng and Jianlu Wei.

Raising animals: Shaoyi Wang and Huichao Tian.

Acquisition of data: Shaoyi Wang, Hong Ding and Xiaocong Zhou.

Analysis and interpretation of data: Shaoyi Wang and Jianlu Wei.

Statistical analysis: Shaoyi Wang.

Drafting of the manuscript: Shaoyi Wang, Jianlu Wei, and Yuchen Fan.

Compliance with Ethical Standards

Patients involved in the study provided consent, and the study was approved by medical ethics regulations of the Medical Ethical Committee of Qilu Hospital of Shandong University

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Andersson, G.B., H.S. An, Oegema TR Jr, and L.A. Setton. 2006. Intervertebral disc degeneration. Summary of an AAOS/NIH/ORS workshop, September 2005. The Journal of Bone and Joint Surgery. American Volume 88 (4): 895–899.PubMedGoogle Scholar
  2. 2.
    Gautschi, O.P., M.V. Corniola, N.R. Smoll, H. Joswig, K. Schaller, G. Hildebrandt, and M.N. Stienen. 2016. Sex differences in subjective and objective measures of pain, functional impairment, and health-related quality of life in patients with lumbar degenerative disc disease. Pain 157 (5): 1065–1071.CrossRefPubMedGoogle Scholar
  3. 3.
    Molinos, M., C.R. Almeida, J. Caldeira, C. Cunha, R.M. Goncalves, and M.A. Barbosa. 2015. Inflammation in intervertebral disc degeneration and regeneration. Journal of the Royal Society, Interface 12 (104): 20141191.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Feng, C., H. Liu, M. Yang, Y. Zhang, B. Huang, and Y. Zhou. 2016. Disc cell senescence in intervertebral disc degeneration: Causes and molecular pathways. Cell Cycle 15 (13): 1674–1684.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Podichetty, V.K. 2007. The aging spine: The role of inflammatory mediators in intervertebral disc degeneration. Cellular and Molecular Biology (Noisy-le-Grand, France) 53 (5): 4–18.Google Scholar
  6. 6.
    Andrade, P., et al. 2011. Tumor necrosis factor-alpha levels correlate with postoperative pain severity in lumbar disc hernia patients: opposite clinical effects between tumor necrosis factor receptor 1 and 2. Pain 152 (11): 2645–2652.CrossRefPubMedGoogle Scholar
  7. 7.
    Shamji, M.F., L.A. Setton, W. Jarvis, S. So, J. Chen, L. Jing, R. Bullock, R.E. Isaacs, C. Brown, and W.J. Richardson. 2010. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis and Rheumatism 62 (7): 1974–1982.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Phillips, K.L., et al. 2015. Potential roles of cytokines and chemokines in human intervertebral disc degeneration: Interleukin-1 is a master regulator of catabolic processes. Osteoarthritis and Cartilage 23 (7): 1165–1177.CrossRefPubMedGoogle Scholar
  9. 9.
    Wei, J., C.J. Liu, and Z. Li. 2014. ADAMTS-18: A metalloproteinase with multiple functions. Frontiers in Bioscience (Landmark Edition) 19: 1456–1467.CrossRefGoogle Scholar
  10. 10.
    Bertram, H., A. Nerlich, G. Omlor, F. Geiger, G. Zimmermann, and J. Fellenberg. 2009. Expression of TRAIL and the death receptors DR4 and DR5 correlates with progression of degeneration in human intervertebral disks. Modern Pathology 22 (7): 895–905.CrossRefPubMedGoogle Scholar
  11. 11.
    Hoyland, J.A., C. Le Maitre, and A.J. Freemont. 2008. Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatology (Oxford) 47 (6): 809–814.CrossRefGoogle Scholar
  12. 12.
    Wang, H., M. Schiltenwolf, and M. Buchner. 2008. The role of TNF-alpha in patients with chronic low back pain-a prospective comparative longitudinal study. The Clinical Journal of Pain 24 (3): 273–278.CrossRefPubMedGoogle Scholar
  13. 13.
    Ortiz, L.A., et al. 2001. Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis. American Journal of Respiratory and Critical Care Medicine 163 (1): 244–252.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhu, J., C. Nathan, W. Jin, D. Sim, G.S. Ashcroft, S.M. Wahl, L. Lacomis, H. Erdjument-Bromage, P. Tempst, C.D. Wright, and A. Ding. 2002. Conversion of proepithelin to epithelins: Roles of SLPI and elastase in host defense and wound repair. Cell 111 (6): 867–878.CrossRefPubMedGoogle Scholar
  15. 15.
    He, Z., C.H.P. Ong, J. Halper, and A. Bateman. 2003. Progranulin is a mediator of the wound response. Nature Medicine 9 (2): 225–229.CrossRefPubMedGoogle Scholar
  16. 16.
    Martens, L.H., J. Zhang, S.J. Barmada, P. Zhou, S. Kamiya, B. Sun, S.W. Min, L. Gan, S. Finkbeiner, E.J. Huang, and R.V. Farese Jr. 2012. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. The Journal of Clinical Investigation 122 (11): 3955–3959.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tang, W., Y. Lu, Q.Y. Tian, Y. Zhang, F.J. Guo, G.Y. Liu, N.M. Syed, Y. Lai, E.A. Lin, L. Kong, J. Su, F. Yin, A.H. Ding, A. Zanin-Zhorov, M.L. Dustin, J. Tao, J. Craft, Z. Yin, J.Q. Feng, S.B. Abramson, X.P. Yu, and C.J. Liu. 2011. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332 (6028): 478–484.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jian, J., S. Zhao, Q. Tian, E. Gonzalez-Gugel, J.J. Mundra, S.M.Z. Uddin, B. Liu, B. Richbourgh, R. Brunetti, and C.J. Liu. 2013. Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains. FEBS Letters 587 (21): 3428–3436.CrossRefPubMedGoogle Scholar
  19. 19.
    Li, M., Y. Liu, F. Xia, Z. Wu, L. Deng, R. Jiang, and F.J. Guo. 2014. Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2. Cellular Signalling 26 (7): 1539–1548.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang, X.D., and S.C. Sun. 2015. Targeting signaling factors for degradation, an emerging mechanism for TRAF functions. Immunological Reviews 266 (1): 56–71.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wei, F., et al. 2014. PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Scientific Reports 4: 7023.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yang, F., V.Y.L. Leung, K.D.K. Luk, D. Chan, and K.M.C. Cheung. 2009. Injury-induced sequential transformation of notochordal nucleus pulposus to chondrogenic and fibrocartilaginous phenotype in the mouse. The Journal of Pathology 218 (1): 113–121.CrossRefPubMedGoogle Scholar
  23. 23.
    Wei, J.L., W. Fu, A. Hettinghouse, W.J. He, K.E. Lipson, and C.J. Liu. 2018. ADAMTS-12 protects against inflammatory arthritis through interacting with and inactivating proinflammatory CTGF. Arthritis & Rhematology.  https://doi.org/10.1002/art.40552
  24. 24.
    Weber, M.S., T. Prod'homme, S. Youssef, S.E. Dunn, C.D. Rundle, L. Lee, J.C. Patarroyo, O. Stüve, R.A. Sobel, L. Steinman, and S.S. Zamvil. 2007. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nature Medicine 13 (8): 935–943.CrossRefPubMedGoogle Scholar
  25. 25.
    Fu, W., W. Hu, L. Shi, J.J. Mundra, G.Z. Xiao, M.L. Dustin, and C.J. Liu. 2017. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. The FASEB Journal 31 (4): 1354–1367.CrossRefPubMedGoogle Scholar
  26. 26.
    Akitsu, A., H. Ishigame, S. Kakuta, S.H. Chung, S. Ikeda, K. Shimizu, S. Kubo, Y. Liu, M. Umemura, G. Matsuzaki, Y. Yoshikai, S. Saijo, and Y. Iwakura. 2015. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vgamma6(+)gammadelta T cells. Nature Communications 6: 7464.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Li, J.K., L. Nie, Y.P. Zhao, Y.Q. Zhang, X. Wang, S.S. Wang, Y. Liu, H. Zhao, and L. Cheng. 2016. IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells. Journal of Translational Medicine 14: 77.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang, W., L. Nie, Y. Wang, X.P. Wang, H. Zhao, S. Dongol, S. Maharjan, and L. Cheng. 2013. CCL20 secretion from the nucleus pulposus improves the recruitment of CCR6-expressing Th17 cells to degenerated IVD tissues. PLoS One 8 (6): e66286.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cheng, L., W. Fan, B. Liu, X. Wang, and L. Nie. 2013. Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity. Injury 44 (12): 1805–1810.CrossRefPubMedGoogle Scholar
  30. 30.
    Hossein-Nezhad, A., K. Mirzaei, H. Ansar, G. Khooshechin, Z. Ahmadivand, and S.A. Keshavarz. 2012. Mutual role of PGRN/TNF-alpha on osteopenia developing in obesity’s inflammation state. Minerva Medica 103 (3): 165–175.PubMedGoogle Scholar
  31. 31.
    Wu, X., Y. Liu, X. Guo, W. Zhou, L. Wang, J. Shi, Y. Tao, M. Zhu, D. Geng, H. Yang, and H. Mao. 2018. Prolactin inhibits the progression of intervertebral disc degeneration through inactivation of the NF-kappaB pathway in rats. Cell Death & Disease 9 (2): 98.CrossRefGoogle Scholar
  32. 32.
    Wei, J., B. Richbourgh, T. Jia, and C. Liu. 2014. ADAMTS-12: A multifaced metalloproteinase in arthritis and inflammation. Mediators of Inflammation 2014: 649718.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Molinos, M., C.R. Almeida, J. Caldeira, C. Cunha, R.M. Gonçalves, and M.A. Barbosa. 2015. Inflammation in intervertebral disc degeneration and regeneration. Journal of the Royal Society, Interface 12 (108): 20150429.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wang, J., D. Markova, D.G. Anderson, Z. Zheng, I.M. Shapiro, and M.V. Risbud. 2011. TNF-alpha and IL-1beta promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. The Journal of Biological Chemistry 286 (46): 39738–39749.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Purmessur, D., B.A. Walter, P.J. Roughley, D.M. Laudier, A.C. Hecht, and J. Iatridis. 2013. A role for TNFalpha in intervertebral disc degeneration: A non-recoverable catabolic shift. Biochemical and Biophysical Research Communications 433 (1): 151–156.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dudek, M., N. Yang, J.P.D. Ruckshanthi, J. Williams, E. Borysiewicz, P. Wang, A. Adamson, J. Li, J.F. Bateman, M.R. White, R.P. Boot-Handford, J.A. Hoyland, and Q.J. Meng. 2017. The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration. Annals of the Rheumatic Diseases 76 (3): 576–584.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhao, Y.P., B. Liu, Q.Y. Tian, J.L. Wei, B. Richbourgh, and C.J. Liu. 2015. Progranulin protects against osteoarthritis through interacting with TNF-alpha and beta-catenin signalling. Annals of the Rheumatic Diseases 74 (12): 2244–2253.CrossRefPubMedGoogle Scholar
  38. 38.
    Jian, J., G. Li, A. Hettinghouse, and C. Liu. 2018. Progranulin: A key player in autoimmune diseases. Cytokine 101: 48–55.CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao, Y.P., J.L. Wei, Q.Y. Tian, A.T. Liu, Y.S. Yi, T.A. Einhorn, and C.J. Liu. 2016. Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFalpha signaling. Scientific Reports 6: 20909.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ding, H., J. Wei, Y. Zhao, Y. Liu, L. Liu, and L. Cheng. 2017. Progranulin derived engineered protein Atsttrin suppresses TNF-alpha-mediated inflammation in intervertebral disc degenerative disease. Oncotarget 8 (65): 109692–109702.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tian, Q., et al. 2014. Three TNFR-binding domains of PGRN act independently in inhibition of TNF-alpha binding and activity. Frontiers in Bioscience (Landmark Edition) 19: 1176–1185.CrossRefGoogle Scholar
  42. 42.
    Zhao, Y.P., Q.Y. Tian, B. Liu, J. Cuellar, B. Richbourgh, T.H. Jia, and C.J. Liu. 2015. Progranulin knockout accelerates intervertebral disc degeneration in aging mice. Scientific Reports 5: 9102.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Matsubara, T., A. Mita, K. Minami, T. Hosooka, S. Kitazawa, K. Takahashi, Y. Tamori, N. Yokoi, M. Watanabe, E.I. Matsuo, O. Nishimura, and S. Seino. 2012. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metabolism 15 (1): 38–50.CrossRefPubMedGoogle Scholar
  44. 44.
    Zhao, Y.P., Q.Y. Tian, and C.J. Liu. 2013. Progranulin deficiency exaggerates, whereas progranulin-derived Atsttrin attenuates, severity of dermatitis in mice. FEBS Letters 587 (12): 1805–1810.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Higuchi, Y., C. McTiernan, C.B. Frye, B. McGowan, T.O. Chan, and A.M. Feldman. 2004. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy. Circulation 109 (15): 1892–1897.CrossRefPubMedGoogle Scholar
  46. 46.
    Wei, J.L., W. Fu, Y.J. Ding, A. Hettinghouse, M. Lendhey, R. Schwarzkopf, O.D. Kennedy, and C.J. Liu. 2017. Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. Arthritis Research & Therapy 19 (1): 280.CrossRefGoogle Scholar
  47. 47.
    Zhang, Y., L. Liu, S. Wang, Y. Zhao, Y. Liu, J. Li, L. Nie, and L. Cheng. 2016. Production of CCL20 on nucleus pulposus cells recruits IL-17-producing cells to degenerated IVD tissues in rat models. Journal of Molecular Histology 47 (1): 81–89.CrossRefPubMedGoogle Scholar
  48. 48.
    Wei, J., A. Hettinghouse, and C. Liu. 2016. The role of progranulin in arthritis. Annals of the New York Academy of Sciences 1383 (1): 5–20.CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Shaoyi Wang
    • 1
    • 2
  • Jianlu Wei
    • 1
  • Yuchen Fan
    • 2
  • Hong Ding
    • 1
    • 2
  • Huichao Tian
    • 1
    • 2
  • Xiaocong Zhou
    • 2
  • Lei Cheng
    • 1
    Email author
  1. 1.Department of OrthopaedicsQilu Hospital of Shandong UniversityJinanPeople’s Republic of China
  2. 2.School of MedicineShandong UniversityJinanChina

Personalised recommendations