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GDF11 Antagonizes Psoriasis-like Skin Inflammation via Suppression of NF-κB Signaling Pathway

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Abstract

Growth differentiation factor-11 (GDF11) is a key member of the transforming growth factor β (TGF-β) superfamily, which plays a momentous role in both normal physiological processes and pathophysiology processes. Recently, it was reported that GDF11 was closely associated with several inflammatory conditions and protected against development of inflammation. Psoriasis-like skin inflammation is a common skin inflammatory disease, yet much is unknown about the underlying mechanisms. In this study, we investigated the expression pattern of GDF11 in two psoriasis-like skin inflammation mice models and tumor necrosis factor-α (TNF-α)-induced RAW264.7 macrophages. Furthermore, RAW264.7 cell was cultured, and GDF11 antagonized the inflammatory function of TNF-α in vitro. Moreover, imiquimod-induced mice model and IL-23-induced mice model were established to investigate the anti-inflammatory role of GDF11 in vivo. As a result, the administration of GDF11 remarkably attenuated the severity of skin inflammation in both two mice models. Additionally, the activation of nuclear NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling pathway was repressed by GDF11 treatment. Collectively, GDF11 may represent a promising molecular target for the prevention and treatment of psoriasis-like skin inflammation.

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References

  1. Lee, Y.S., and S.J. Lee. 2013. Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proceedings of the National Academy of Sciences of the United States of America 110: E3713–E3722.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fingert, J.H., R.A. Honkanen, S.P. Shankar, L.M. Affatigato, M.A. Ehlinger, M.D. Moore, L.M. Jampol, V.C. Sheffield, E.M. Stone, and W.L. Alward. 2007. Familial cavitary optic disk anomalies: identification of a novel genetic locus. American Journal of Ophthalmology 143: 795–800.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zimmers, T.A., Y. Jiang, M. Wang, T.W. Liang, J.E. Rupert, E.D. Au, F.E. Marino, M.E. Couch, and L.G. Koniaris. 2017. Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Research in Cardiology 112: 48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang, Y., Y. Wei, D. Liu, F. Liu, X. Li, L. Pan, Y. Pang, and D. Chen. 2017. Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget 8: 81604–81616.

    PubMed  PubMed Central  Google Scholar 

  5. Jamaiyar, A., W. Wan, D.M. Janota, M.K. Enrick, W.M. Chilian, and L. Yin. 2017. The versatility and paradox of GDF 11. Pharmacology & Therapeutics 175: 28–34.

    Article  CAS  Google Scholar 

  6. Yang, R., S. Fu, L. Zhao, B. Zhen, L. Ye, X. Niu, X. Li, P. Zhang, and J. Bai. 2017. Quantitation of circulating GDF-11 and beta2-MG in aged patients with age-related impairment in cognitive function. Clinical Science (London, England) 131: 1895–1904.

    Article  CAS  Google Scholar 

  7. Mei, W., G. Xiang, Y. Li, H. Li, L. Xiang, J. Lu, L. Xiang, J. Dong, and M. Liu. 2016. GDF11 protects against endothelial injury and reduces atherosclerotic lesion formation in apolipoprotein E-null mice. Molecular Therapy 24: 1926–1938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roudsari, M.R., R. Karimi, S. Sohrabvandi, and A.M. Mortazavian. 2015. Health effects of probiotics on the skin. Critical Reviews in Food Science and Nutrition 55: 1219–1240.

    Article  PubMed  Google Scholar 

  9. Jain, A., P. Jain, J. Kurmi, D. Jain, R. Jain, S. Chandel, A. Sahu, N. Mody, S. Upadhaya, and A. Jain. 2014. Novel strategies for effective transdermal drug delivery: a review. Critical Reviews in Therapeutic Drug Carrier Systems 31: 219–272.

    Article  CAS  PubMed  Google Scholar 

  10. Lim, X., R, Nusse. 2013. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harbor Perspectives in Biology 5: 152–158.

  11. Frombach, J., A. Sonnenburg, B.D. Krapohl, T. Zuberbier, M. Peiser, R. Stahlmann, and M. Schreiner. 2018. Lymphocyte surface markers and cytokines are suitable for detection and potency assessment of skin-sensitizing chemicals in an in vitro model of allergic contact dermatitis: the LCSA-ly. Archives of Toxicology 92: 1495–1505.

    Article  CAS  PubMed  Google Scholar 

  12. Phillips, G.S., A. Freites-Martinez, M. Hsu, A. Skripnik Lucas, D.M. Barrios, K. Ciccolini, M.A. Marchetti, L. Deng, P.L. Myskowski, E.H. Lee, et al. 2017. Inflammatory dermatoses, infections, and drug eruptions are the most common skin conditions in hospitalized cancer patients. Journal of the American Academy of Dermatology 78: 1102–1109.

  13. Vukmanovic, S., and N. Sadrieh. 2017. Skin sensitizers in cosmetics and beyond: potential multiple mechanisms of action and importance of T-cell assays for in vitro screening. Critical Reviews in Toxicology 47: 415–432.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao, Y., W. Wang, X. Wu, X. Ma, R. Qu, X. Chen, C. Liu, Y. Liu, X. Wang, P. Yan, H. Zhang, J. Pan, and W. Li. 2017. Mangiferin antagonizes TNF-alpha-mediated inflammatory reaction and protects against dermatitis in a mice model. International Immunopharmacology 45: 174–179.

    Article  CAS  PubMed  Google Scholar 

  15. Talreja, J., and L. Samavati. 2018. K63-linked polyubiquitination on TRAF6 regulates LPS-mediated MAPK activation, cytokine production, and bacterial clearance in toll-like receptor 7/8 primed murine macrophages. Frontiers in Immunology 9: 279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Das, T., Z. Chen, R.W. Hendriks, and M. Kool. 2018. A20/tumor necrosis factor alpha-induced protein 3 in immune cells controls development of autoinflammation and autoimmunity: lessons from mouse models. Frontiers in Immunology 9: 104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Suto, H., A. Nambu, H. Morita, S. Yamaguchi, T. Numata, T. Yoshizaki, E. Shimura, K. Arae, Y. Asada, K. Motomura, M. Kaneko, T. Abe, A. Matsuda, Y. Iwakura, K. Okumura, H. Saito, K. Matsumoto, K. Sudo, S. Nakae. 2018. IL-25 enhances Th17 cell-mediated contact dermatitis by promoting IL-1beta production by dermal dendritic cells. The Journal of Allergy and Clinical Immunology 18: 30326.

  18. Revu, S., J. Wu, M. Henkel, N. Rittenhouse, A. Menk, G.M. Delgoffe, A.C. Poholek, and M.J. McGeachy. 2018. IL-23 and IL-1beta drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation. Cell Reports 22: 2642–2653.

    Article  CAS  PubMed  Google Scholar 

  19. Adela, R., and S.K. Banerjee. 2015. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015: 490842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang, S.J., J.Q. Yan, H. Luo, L.Y. Zhou, and J.G. Luo. 2018. IL-33/ST2 signaling contributes to radicular pain by modulating MAPK and NF-kappaB activation and inflammatory mediator expression in the spinal cord in rat models of noncompressive lumber disk herniation. Journal of Neuroinflammation 15: 12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morris, G., A.J. Walker, M. Berk, M. Maes, B.K. Puri. 2017. Cell death pathways: a novel therapeutic approach for neuroscientists. Molecular Neurobiology 6: 1–20.

  22. Ueyama, A., M. Yamamoto, K. Tsujii, Y. Furue, C. Imura, M. Shichijo, and K. Yasui. 2014. Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod. The Journal of Dermatology 41: 135–143.

    Article  CAS  PubMed  Google Scholar 

  23. Alyoussef, A. 2015. Arjunolic acid protects against DNCB-induced atopic dermatitis-like symptoms in mice by restoring a normal cytokine balance. European Cytokine Network 26: 38–45.

    PubMed  Google Scholar 

  24. Riol-Blanco, L., J. Ordovas-Montanes, M. Perro, E. Naval, A. Thiriot, D. Alvarez, S. Paust, J.N. Wood, and U.H. von Andrian. 2014. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510: 157–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, W., Z. Li, Q. Meng, P. Zhang, P. Yan, Z. Zhang, H. Zhang, J. Pan, Y. Zhai, Y. Liu, X. Wang, W. Li, and Y. Zhao. 2016. Chronic calcium channel inhibitor verapamil antagonizes TNF-alpha-mediated inflammatory reaction and protects against inflammatory arthritis in mice. Inflammation 39: 1624–1634.

    Article  CAS  PubMed  Google Scholar 

  26. Malissen, B., S. Tamoutounour, and S. Henri. 2014. The origins and functions of dendritic cells and macrophages in the skin. Nature Reviews. Immunology 14: 417–428.

    Article  CAS  PubMed  Google Scholar 

  27. Tamoutounour, S., M. Guilliams, F. Montanana Sanchis, H. Liu, D. Terhorst, C. Malosse, E. Pollet, L. Ardouin, H. Luche, C. Sanchez, M. Dalod, B. Malissen, and S. Henri. 2013. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39: 925–938.

    Article  CAS  PubMed  Google Scholar 

  28. Alvarez-Jimenez, V.D., K. Leyva-Paredes, M. Garcia-Martinez, L. Vazquez-Flores, V.G. Garcia-Paredes, M. Campillo-Navarro, I. Romo-Cruz, V.H. Rosales-Garcia, J. Castaneda-Casimiro, S. Gonzalez-Pozos, et al. 2018. Extracellular vesicles released from Mycobacterium tuberculosis-infected neutrophils promote macrophage autophagy and decrease intracellular mycobacterial survival. Frontiers in Immunology 9: 272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rojas Marquez, J.D., Y. Ana, R.E. Baigorri, C.C. Stempin, and F.M. Cerban. 2018. Mammalian target of rapamycin inhibition in Trypanosoma cruzi-infected macrophages leads to an intracellular profile that is detrimental for infection. Frontiers in Immunology 9: 313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chong, S.Z., K.W. Tan, F.H. Wong, Y.L. Chua, Y. Tang, L.G. Ng, V. Angeli, and D.M. Kemeny. 2014. CD8 T cells regulate allergic contact dermatitis by modulating CCR2-dependent TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells. The Journal of Investigative Dermatology 134: 666–676.

    Article  CAS  PubMed  Google Scholar 

  31. Chen, H., C. Lu, H. Liu, M. Wang, H. Zhao, Y. Yan, and L. Han. 2017. Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-kappaB pathway. International Immunopharmacology 48: 110–117.

    Article  CAS  PubMed  Google Scholar 

  32. Augustin, H., J. Adcott, C.J.H. Elliott, and L. Partridge. 2017. Complex roles of myoglianin in regulating adult performance and lifespan. Fly (Austin) 11: 284–289.

    Article  Google Scholar 

  33. Poggioli, T., A. Vujic, P. Yang, C. Macias-Trevino, A. Uygur, F.S. Loffredo, J.R. Pancoast, M. Cho, J. Goldstein, R.M. Tandias, E. Gonzalez, R.G. Walker, T.B. Thompson, A.J. Wagers, Y.W. Fong, and R.T. Lee. 2016. Circulating growth differentiation factor 11/8 levels decline with age. Circulation Research 118: 29–37.

    Article  CAS  PubMed  Google Scholar 

  34. Sinha, M., Y.C. Jang, J. Oh, D. Khong, E.Y. Wu, R. Manohar, C. Miller, S.G. Regalado, F.S. Loffredo, J.R. Pancoast, M.F. Hirshman, J. Lebowitz, J.L. Shadrach, M. Cerletti, M.J. Kim, T. Serwold, L.J. Goodyear, B. Rosner, R.T. Lee, and A.J. Wagers. 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344: 649–652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Loffredo, F.S., M.L. Steinhauser, S.M. Jay, J. Gannon, J.R. Pancoast, P. Yalamanchi, M. Sinha, C. Dall'Osso, D. Khong, J.L. Shadrach, et al. 2013. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153: 828–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hou, Y., L. Zhu, H. Tian, H.X. Sun, R. Wang, L. Zhang, Y. Zhao. 2018. IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis. Protein & Cell 5: 1–12.

  37. Homann, A., N. Rockendorf, A. Kromminga, A. Frey, T.A. Platts-Mills, and U. Jappe. 2017. Glycan and peptide IgE epitopes of the TNF-alpha blockers infliximab and adalimumab-precision diagnostics by cross-reactivity immune profiling of patient sera. Theranostics 7: 4699–4709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martinez-Escala, M.E., A.L. Posligua, H. Wickless, A. Rutherford, K.A. Sable, B. Rubio-Gonzalez, X.A. Zhou, J.B. Kaplan, B. Pro, J. Choi, C. Querfeld, S.T. Rosen, and J. Guitart. 2018. Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor alpha therapy. Journal of the American Academy of Dermatology 78: 1068–1076.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Qu, R., X. Chen, W. Wang, C. Qiu, M. Ban, L. Guo, K. Vasilev, J. Chen, W. Li, and Y. Zhao. 2018. Ghrelin protects against osteoarthritis through interplay with Akt and NF-kappaB signaling pathways. The FASEB Journal 32: 1044–1058.

    Article  CAS  PubMed  Google Scholar 

  40. Bech, R., B. Jalilian, R. Agger, L. Iversen, M. Erlandsen, K. Otkjaer, C. Johansen, S.R. Paludan, C.A. Rosenberg, K. Kragballe, and T. Vorup-Jensen. 2016. Interleukin 20 regulates dendritic cell migration and expression of co-stimulatory molecules. Molecular and Cellular Therapies 4 (1): 1.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hung, C.H., C.H. Wang, H.H. Cheng, J.W. Liao, Y.T. Chen, Y.W. Chao, J.L. Jiang, C.C. Lee. 2018. Baicalin ameliorates imiquimod-induced psoriasis-like inflammation in mice. Planta Medica. https://doi.org/10.1055/a-0622-8242.

  42. Rather, I.A., V.K. Bajpai, Y.S. Huh, Y.K. Han, E.A. Bhat, J. Lim, W.K. Paek, and Y.H. Park. 2018. Probiotic lactobacillus sakei proBio-65 extract ameliorates the severity of imiquimod induced psoriasis-like skin inflammation in a mouse model. Frontiers in Microbiology 9: 1021.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wu, R., J. Zeng, J. Yuan, X. Deng, Y. Huang, L. Chen, P. Zhang, H. Feng, Z. Liu, Z. Wang, X. Gao, H. Wu, H. Wang, Y. Su, M. Zhao, and Q. Lu. 2018. MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. The Journal of Clinical Investigation 128: 2551–2568.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Li, P., Y. Li, H. Jiang, Y. Xu, X. Liu, B. Che, J. Tang, G. Liu, Y. Tang, W. Zhou, L. Zhang, C. Dong, H. Chen, K. Zhang, and Z. du. 2018. Glabridin, an isoflavan from licorice root, ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice. International Immunopharmacology 59: 243–251.

    Article  CAS  PubMed  Google Scholar 

  45. Leite Dantas, R., D. Masemann, T. Schied, V. Bergmeier, T. Vogl, K. Loser, B. Brachvogel, G. Varga, S. Ludwig, and V. Wixler. 2016. Macrophage-mediated psoriasis can be suppressed by regulatory T lymphocytes. The Journal of Pathology 240: 366–377.

    Article  CAS  PubMed  Google Scholar 

  46. Raguz, J., I. Jeric, T. Niault, J.D. Nowacka, S.E. Kuzet, C. Rupp, I. Fischer, S. Biggi, T. Borsello, M. Baccarini. 2016. Epidermal RAF prevents allergic skin disease. Elife 5: 14012.

  47. Han, Y.P., T.L. Tuan, H. Wu, M. Hughes, and W.L. Garner. 2001. TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP. Journal of Cell Science 114: 131–139.

    CAS  PubMed  Google Scholar 

  48. Chian, C.F., C.H. Chiang, C.H. Chuang, and S.L. Liu. 2014. Inhibitor of nuclear factor-kappaB, SN50, attenuates lipopolysaccharide-induced lung injury in an isolated and perfused rat lung model. Translational Research 163: 211–220.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Dr. Chao Liu and Professor Shaohua Liu for their scientific input and advice. The authors thank Hua Zhao, Hao Li, and Songgang Wang for providing secretarial assistance and technical support.

Funding

This work was supported by Key Research and Development Projects of Shandong Province (Grant 2015GSF118115), the Natural Science Foundation of Shandong Province (Grants BS2014YY048 and BS2015SW028), the Major Project of Science and Technology of Shandong Province (2015ZDJS04001), and the National Natural Science Foundation of China (Grants 81501880 and 81602761).

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Authors and Affiliations

  1. Department of Orthopedics, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, People’s Republic of China

    Wenhan Wang, Xi Wang, Mengchen Zhang, Yayun Zhang, Changjun Chen, Xin Pan & Yunpeng Zhao

  2. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China

    Wenhan Wang, Ruize Qu, Xi Wang, Mengchen Zhang, Yayun Zhang, Changjun Chen, Xiaomin Chen, Cheng Qiu & Jiayi Li

  3. Department of Pathology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, People’s Republic of China

    Weiwei Li

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  1. Wenhan Wang
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  2. Ruize Qu
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  3. Xi Wang
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  7. Xiaomin Chen
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  8. Cheng Qiu
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  9. Jiayi Li
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  10. Xin Pan
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  11. Weiwei Li
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  12. Yunpeng Zhao
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Contributions

W. Li and Y. Zhao conceived and designed the experiments; W. Wang, R. Qu, X. Wang, M. Zhang, Y. Zhang, C. Chen, X. Chen, C. Qiu, and J. Li performed the experiments; W. Wang, X. Pan, and Y. Zhao analyzed the data; and W. Li and Y. Zhao contributed reagents, materials, and analysis tools.

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Correspondence to Weiwei Li or Yunpeng Zhao.

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The authors declare that they have no conflict of interest.

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All animal experiments were approved by the Shandong University Animal Care and Use Committee (Shandong, China).

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Wang, W., Qu, R., Wang, X. et al. GDF11 Antagonizes Psoriasis-like Skin Inflammation via Suppression of NF-κB Signaling Pathway. Inflammation 42, 319–330 (2019). https://doi.org/10.1007/s10753-018-0895-3

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