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EGR1 Mediated Reduction of Fibroblast Secreted-TGF-β1 Exacerbated CD8+ T Cell Inflammation and Migration in Vitiligo

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Abstract

Vitiligo is a T cell-mediated depigment skin disease caused by the complex interplay between melanocyte dysfunction, environmental stimulation, and dysregulated immune signals. Transforming growth factor-β1 (TGF-β1), which typically derives from regulatory T cells, has long been identified at low levels in the peripheral system of vitiligo patients. Here, through RNA-sequencing and transcription factor enrichment, we revealed that in response to CD8+ T cell-secreted interferon-gamma (IFN-γ), stromal fibroblast downregulates early growth response 1 (EGR1) activity, leading to TGF-β1 deficiency. The defective immune regulation loop further exacerbated local CD8+ T cell inflammation and promoted inflammatory cell migration in vitiligo. Thus, fibroblast-derived TGF-β1 plays an important stromal signal in vitiligo pathogenesis.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author, Aie Xu.

References

  1. Ezzedine, K., H.W. Lim, T. Suzuki, I. Katayama, I. Hamzavi, C.C. Lan, B.K. Goh, T. Anbar, C. Silva de Castro, A.Y. Lee, D. Parsad, N.V. Geel, I.C. Le Poole, et al. 2012. Revised classification/nomenclature of vitiligo and related issues: the vitiligo global issues consensus conference. Pigment Cell & Melanoma Research 25 (3): E1–13.

  2. Ramakrishna, P., and T. Rajni. 2014. Psychiatric morbidity and quality of life in vitiligo patients. Indian Journal of Psychological Medicine 36 (3): 302–303.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Manga, P., N. Elbuluk, and S.J. Orlow. 2016. Recent advances in understanding vitiligo. F1000Research 5.

  4. Boissy, R.E., and P. Manga. 2004. On the etiology of contact/occupational vitiligo. Pigment Cell Research 17 (3): 208–214.

    Article  CAS  PubMed  Google Scholar 

  5. Tzavlaki, K., and A. Moustakas. 2020. Tgf-beta signaling. Biomolecules 10 (3).

  6. Kubiczkova, L., L. Sedlarikova, R. Hajek, and S. Sevcikova. 2012. Tgf-beta - an excellent servant but a bad master. Journal of Translational Medicine 10: 183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen, W. 2023. Tgf-beta regulation of t cells. Annual Review of Immunology 41: 483–512.

    Article  PubMed  Google Scholar 

  8. Li, M.O., and R.A. Flavell. 2008. Tgf-beta: A master of all t cell trades. Cell 134 (3): 392–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, M.O., S. Sanjabi, and R.A. Flavell. 2006. Transforming growth factor-beta controls development, homeostasis, and tolerance of t cells by regulatory t cell-dependent and -independent mechanisms. Immunity 25 (3): 455–471.

    Article  CAS  PubMed  Google Scholar 

  10. Robinson, R.T., and J.D. Gorham. 2007. Tgf-beta 1 regulates antigen-specific cd4+ t cell responses in the periphery. The Journal of Immunology 179 (1): 71–79.

    Article  CAS  PubMed  Google Scholar 

  11. Sakaguchi, S., T. Yamaguchi, T. Nomura, and M. Ono. 2008. Regulatory t cells and immune tolerance. Cell 133 (5): 775–787.

    Article  CAS  PubMed  Google Scholar 

  12. Oh, S.A., and M.O. Li. 2013. Tgf-beta: Guardian of t cell function. The Journal of Immunology 191 (8): 3973–3979.

    Article  CAS  PubMed  Google Scholar 

  13. Dwivedi, M., N.C. Laddha, P. Arora, Y.S. Marfatia, and R. Begum. 2013. Decreased regulatory t-cells and cd4(+) /cd8(+) ratio correlate with disease onset and progression in patients with generalized vitiligo. Pigment Cell & Melanoma Research 26 (4): 586–591.

    Article  CAS  Google Scholar 

  14. Giri, P.S., M. Dwivedi, and R. Begum. 2020. Decreased suppression of cd8(+) and cd4(+) t cells by peripheral regulatory t cells in generalized vitiligo due to reduced nfatc1 and foxp3 proteins. Experimental Dermatology 29 (8): 759–775.

    Article  CAS  PubMed  Google Scholar 

  15. Giri, P.S., M. Dwivedi, N.C. Laddha, R. Begum, and A.H. Bharti. 2020. Altered expression of nuclear factor of activated t cells, forkhead box p3, and immune-suppressive genes in regulatory t cells of generalized vitiligo patients. Pigment Cell & Melanoma Research 33 (4): 566–578.

    Article  CAS  Google Scholar 

  16. Allanore, Y., R. Simms, O. Distler, M. Trojanowska, J. Pope, C.P. Denton, and J. Varga. 2015. Systemic sclerosis. Nat Rev Dis Primers 1: 15002.

    Article  PubMed  Google Scholar 

  17. Nuchel, J., S. Ghatak, A.V. Zuk, A. Illerhaus, M. Morgelin, K. Schonborn, K. Blumbach, S.A. Wickstrom, T. Krieg, G. Sengle, M. Plomann, and B. Eckes. 2018. Tgfb1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy 14 (3): 465–486.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wlaschek, M., P. Maity, E. Makrantonaki, and K. Scharffetter-Kochanek. 2021. Connective tissue and fibroblast senescence in skin aging. The Journal of Investigative Dermatology 141 (4S): 985–992.

    Article  CAS  PubMed  Google Scholar 

  19. Giri, P.S., J. Mistry, and M. Dwivedi. 2022. Meta-analysis of alterations in regulatory t cells’ frequency and suppressive capacity in patients with vitiligo. Journal of Immunology Research 2022: 6952299.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xu, Z., D. Chen, Y. Hu, K. Jiang, H. Huang, Y. Du, W. Wu, J. Wang, J. Sui, W. Wang, L. Zhang, S. Li, C. Li, et al. 2022. Anatomically distinct fibroblast subsets determine skin autoimmune patterns. Nature 601 (7891): 118–124.

    Article  CAS  PubMed  Google Scholar 

  21. Nagai, H., I. Hara, T. Horikawa, M. Oka, S. Kamidono, and M. Ichihashi. 2000. Elimination of cd4(+) t cells enhances anti-tumor effect of locally secreted interleukin-12 on b16 mouse melanoma and induces vitiligo-like coat color alteration. The Journal of Investigative Dermatology 115 (6): 1059–1064.

    Article  CAS  PubMed  Google Scholar 

  22. Rashighi, M., and J.E. Harris. 2017. Vitiligo pathogenesis and emerging treatments. Dermatologic Clinics 35 (2): 257–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Richmond, J.M., M.L. Frisoli, and J.E. Harris. 2013. Innate immune mechanisms in vitiligo: Danger from within. Current Opinion in Immunology 25 (6): 676–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Faraj, S., E.H. Kemp, and D.J. Gawkrodger. 2022. Patho-immunological mechanisms of vitiligo: The role of the innate and adaptive immunities and environmental stress factors. Clinical and Experimental Immunology 207 (1): 27–43.

    Article  PubMed  Google Scholar 

  25. Yang, L., Y. Wei, Y. Sun, W. Shi, J. Yang, L. Zhu, and M. Li. 2015. Interferon-gamma inhibits melanogenesis and induces apoptosis in melanocytes: A pivotal role of cd8+ cytotoxic t lymphocytes in vitiligo. Acta Dermato Venereologica 95 (6): 664–670.

    Article  CAS  PubMed  Google Scholar 

  26. Griffin, M.F., H.E. desJardins-Park, S. Mascharak, M.R. Borrelli, and M.T. Longaker. 2020. Understanding the impact of fibroblast heterogeneity on skin fibrosis. Disease Models & Mechanisms 13 (6).

  27. Correa-Gallegos, D., D. Jiang, and Y. Rinkevich. 2021. Fibroblasts as confederates of the immune system. Immunological Reviews 302 (1): 147–162.

    Article  CAS  PubMed  Google Scholar 

  28. Tu, C.X., W.W. Jin, M. Lin, Z.H. Wang, and M.Q. Man. 2011. Levels of tgf-beta(1) in serum and culture supernatants of cd4(+)cd25 (+) t cells from patients with non-segmental vitiligo. Archives of Dermatological Research 303 (9): 685–689.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou, L., Y.L. Shi, K. Li, I. Hamzavi, T.W. Gao, R.H. Huggins, H.W. Lim, and Q.S. Mi. 2015. Increased circulating th17 cells and elevated serum levels of tgf-beta and il-21 are correlated with human non-segmental vitiligo development. Pigment Cell & Melanoma Research 28 (3): 324–329.

    Article  CAS  Google Scholar 

  30. Gunderson, A.J., T. Yamazaki, K. McCarty, N. Fox, M. Phillips, A. Alice, T. Blair, M. Whiteford, D. O’Brien, R. Ahmad, M.X. Kiely, A. Hayman, T. Crocenzi, et al. 2020. Tgfbeta suppresses cd8(+) t cell expression of cxcr3 and tumor trafficking. Nature Communications 11 (1): 1749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Milbrandt, J. 1987. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238 (4828): 797–799.

    Article  CAS  PubMed  Google Scholar 

  32. Wang, B., H. Guo, H. Yu, Y. Chen, H. Xu, and G. Zhao. 2021. The role of the transcription factor egr1 in cancer. Frontiers in Oncology 11: 642547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jeong, S.H., H.J. Kim, H.J. Ryu, W.I. Ryu, Y.H. Park, H.C. Bae, Y.S. Jang, and S.W. Son. 2013. Zno nanoparticles induce tnf-alpha expression via ros-erk-egr-1 pathway in human keratinocytes. Journal of Dermatological Science 72 (3): 263–273.

    Article  CAS  PubMed  Google Scholar 

  34. Rockel, J.S., S.M. Bernier, and A. Leask. 2009. Egr-1 inhibits the expression of extracellular matrix genes in chondrocytes by tnfalpha-induced mek/erk signalling. Arthritis Research & Therapy 11 (1): R8.

    Article  Google Scholar 

  35. Vaish, V., H. Piplani, C. Rana, K. Vaiphei, and S.N. Sanyal. 2013. Nsaids may regulate egr-1-mediated induction of reactive oxygen species and non-steroidal anti-inflammatory drug-induced gene (nag)-1 to initiate intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer. Molecular and Cellular Biochemistry 378 (1–2): 47–64.

    Article  CAS  PubMed  Google Scholar 

  36. Shin, S.Y., H.W. Kim, H.H. Jang, Y.J. Hwang, J.S. Choe, J.B. Kim, Y. Lim, and Y.H. Lee. 2017. Gamma-oryzanol suppresses cox-2 expression by inhibiting reactive oxygen species-mediated erk1/2 and egr-1 signaling in lps-stimulated raw264.7 macrophages. Biochemical and Biophysical Research Communications 491 (2): 486–492.

  37. Kim, J.H., I.Y. Jeong, Y. Lim, Y.H. Lee, and S.Y. Shin. 2011. Estrogen receptor beta stimulates egr-1 transcription via mek1/erk/elk-1 cascade in c6 glioma cells. BMB Reports 44 (7): 452–457.

    Article  CAS  PubMed  Google Scholar 

  38. Bhattacharyya, S., F. Fang, W. Tourtellotte, and J. Varga. 2013. Egr-1: New conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis). The Journal of Pathology 229 (2): 286–297.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China Joint Fund Project (U22A20310), National Natural Science Foundation of China (82003322), Natural Science Foundation of Zhejiang Province (LY21H110002), and Zhejiang Science and Technology Plan of Traditional Chinese Medicine (2021ZQ075).

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  1. Rong Jin and Hao Xu contributed equally to this work

Authors and Affiliations

  1. Department of Dermatology, Hangzhou Third People’s Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People’s Republic of China

    Rong Jin, Hao Xu, Miaoni Zhou, Fuquan Lin, Wen Xu & Aie Xu

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Contributions

AEX designed the experiments. RJ developed the methodology. RJ and HX performed the experiments, analyzed, interpreted data, statistical analyses, and wrote the manuscript. MNZ revised the manuscript. WX edited and reviewed the manuscript. FQL searched the literature. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Aie Xu.

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Ethics Approval

All patients signed a written informed consent form and the study protocol was approved by the Ethics Committee of Hangzhou Third People's Hospital (approval no. 2023KA015).

All animal experiments complied with ethical regulations. All procedures were approved and supervised by the Subcommittee on Research Animal Care of the Fourth Military Medical University (approval no. KY20213342-1).

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Informed consent was obtained from all individual participants included in the study.

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The authors affirm that human research participants provided informed consent for the publication of the images in Fig. 2e and h.

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The authors declare that they have no competing interests.

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Jin, R., Xu, H., Zhou, M. et al. EGR1 Mediated Reduction of Fibroblast Secreted-TGF-β1 Exacerbated CD8+ T Cell Inflammation and Migration in Vitiligo. Inflammation 47, 503–512 (2024). https://doi.org/10.1007/s10753-023-01922-2

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