2. Academic Validation
  3. FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes

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

  • Cell Mol Immunol. 2023 Jan 25. doi: 10.1038/s41423-023-00973-7.
Wenjuan Yang # 1 2,  Rukun He # 1,  Hao Qu # 3,  Wenwen Lian 1,  Yue Xue 1,  Tao Wang 1 2,  Wenlong Lin 1,  Peishuo Zhu 1,  Meng Xia 4,  Lihua Lai 5,  Qingqing Wang 6 7
Affiliations

Affiliations

  • 1 Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121, Hangzhou, China.
  • 3 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
  • 4 Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China. xiameng.dream@zju.edu.cn.
  • 5 Department of Pharmacology, Zhejiang University School of Medicine, 310058, Hangzhou, China. lailihua@zju.edu.cn.
  • 6 Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, China. wqq@zju.edu.cn.
  • 7 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121, Hangzhou, China. wqq@zju.edu.cn.
  • # Contributed equally.
PMID: 36693922 DOI: 10.1038/s41423-023-00973-7
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.

Keywords

FXYD3; IL-17 signaling; Keratinocytes; Psoriasis; TRAF3.

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