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FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes

Cellular & Molecular Immunology volume 20, pages 292–304 (2023)Cite this article

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Abstract

Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia. However, the regulatory complexity of cytokine and cellular networks still needs to be investigated. Here, we show that the expression of FXYD3, a member of the FXYD domain-containing regulators of Na+/K+ ATPases family, is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod (IMQ)-induced psoriasis. IL-17A, a cytokine important for the development of psoriatic lesions, contributes to FXYD3 expression in human primary keratinocytes. FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model. Importantly, FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes. This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors. Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation. Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.

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Acknowledgements

We thank Prof Xiaojian Wang for sharing the plasmid. We are grateful to Yanwei Li, Jingyao Chen, Qiong Huang and Guifeng Xiao from the Core Facility of Zhejiang University School of Medicine for their technical support. We also thank Jian Wu from Zhejiang University Laboratory Animal Center for daily mouse breeding. We thank the Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, China for support. This work was supported by grants from the National Natural Science Foundation of China (91842103, 31870907, 81930041) and the Natural Science Foundation of Zhejiang Province (Z19H100001).

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  1. These authors contributed equally: Wenjuan Yang, Rukun He, Hao Qu.

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China

    Wenjuan Yang, Rukun He, Wenwen Lian, Yue Xue, Tao Wang, Wenlong Lin, Peishuo Zhu, Meng Xia & Qingqing Wang

  2. Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121, Hangzhou, China

    Wenjuan Yang, Tao Wang & Qingqing Wang

  3. Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China

    Hao Qu

  4. Department of Pharmacology, Zhejiang University School of Medicine, 310058, Hangzhou, China

    Lihua Lai

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Contributions

QW, LL, MX, and WY designed the experiments. WY, RH, and HQ conducted the experiments and prepared the figures. WL, YX, WL, TW, PZ, and MX contributed to all experiments; WY, LL, and QW wrote the paper. All authors read and approved the final paper.

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Correspondence to Meng Xia, Lihua Lai or Qingqing Wang.

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Yang, W., He, R., Qu, H. et al. FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes. Cell Mol Immunol 20, 292–304 (2023). https://doi.org/10.1038/s41423-023-00973-7

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