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Abnormal expression of interleukin-6 is associated with epidermal alternations in localized scleroderma

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Abstract

Objectives

Localized scleroderma (LSc) is a disease characterized by the excessive deposition of collagen and thereby thickening of the dermis. In recent years, studies reported that LSc demonstrated compromised skin barrier related to the progression of the disease. However, human studies examining epidermis in scleroderma are still sparse and lack systematic research. This study aims to investigate the structural and functional changes in the LSc epidermis and further explore the underlying mechanisms, providing a new angle to treat LSc in the clinic.

Methods

A total of 136 skin sites, including lesion and non-lesion control, from 27 LSc patients were analyzed. Ultrasonic testing, trans-epidermal water loss (TEWL), and epidermal hydration were assessed to investigate the structural and functional alternations; correlations between these parameters were analyzed. To explore the underlying mechanism, skin-fibrosis mouse model and cellular model by bleomycin (BLM) were deployed.

Results

The epidermal thickness was markedly increased, with a significant decline of hydration (dryness) in the LSc lesion skin. Epidermal hydration presented a negative correlation with the thickness. TEWL was not altered. The mouse model validated these morphological changes in the epidermis and indicated that interleukin-6 (IL-6) was significantly elevated. Furthermore, cellular study demonstrated that increased phosphorylation of p38 in keratinocyte promoted the secretion of IL-6, stimulating cell proliferation.

Conclusion

This study characterized the epidermal alterations in LSc patients, suggesting that keratinocyte-derived abnormal IL-6 secretion can lead to the thickening of the epidermis, promoting dryness. The topical application of moisturizer may largely relieve dryness and related pruritus, thus improve the quality of life in LSc patients.

Key Points

• Epidermal thickness was increased in LSc lesion skin with declined hydration level.

• Skin fibrosis mouse model validated the epidermal alteration in LSc patient.

• p38-dependent IL-6 overexpression in keratinocyte result in epidermal thickening.

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Funding

This work was supported by National Natural Science Foundation of China (81703097), China Postdoctoral Science Foundation (2017M621365), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5–066).

Author information

Authors and Affiliations

  1. Ministry of Education Key Laboratory of Contemporary Anthropology and Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China

    Xingyu Zhu, Liuyiqi Jiang, Qian Zhong, Xiangzhen Kong, Rui Zhang, Lingxian Zhu, Jiucun Wang & Jingjing Xia

  2. Institute for Six-Sector Economy, Fudan University, Shanghai, China

    Xingyu Zhu

  3. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China

    Qingmei Liu & Wenyu Wu

  4. Department of Skin & Cosmetic Research, Shanghai Skin Disease Hospital, Shanghai, China

    Yimei Tan

  5. Human Phenome Institute, Fudan University, Shanghai, China

    Yimei Tan & Jiucun Wang

  6. Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou, China

    Jingjing Xia

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  1. Xingyu Zhu
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Contributions

JX and XZ designed this study; XZ, QZ, XK, LZ, and RZ assessed skin morphology and physiology; XZ performed the animal and cellular experiments; LJ performed the RNA-seq analysis; YT supervised skin physiology assessment; JX and JW supervised the whole project; XZ and JX drafted the manuscript and substantially revised by JW; QL and WW for the intensive scientific discussion and suggestions.

Corresponding authors

Correspondence to Jiucun Wang or Jingjing Xia.

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Ethics approval

This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Study procedures were reviewed and approved by the Ethics Committee of School of Life Sciences, Fudan University (2017–619). Signed informed consent was obtained from all participants. Animal experiments were performed following the general guidelines, and the protocol was approved by the Animal Care and Use Committee of the School of Life sciences at Fudan University, China.

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Zhu, X., Jiang, L., Zhong, Q. et al. Abnormal expression of interleukin-6 is associated with epidermal alternations in localized scleroderma. Clin Rheumatol 41, 2179–2187 (2022). https://doi.org/10.1007/s10067-022-06127-w

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