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The cytokine CSBF inhibits the IL-17A and TNF-α inflammatory pathways via SUSD2-ACT1 in keratinocytes and alleviates IMQ-induced psoriasis

Cellular & Molecular Immunology volume 22, pages 1109–1122 (2025)Cite this article

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Abstract

Overactivation of inflammatory signaling in keratinocytes is critical for psoriatic skin inflammation, but its regulatory mechanisms remain incompletely understood. Here, we demonstrate that the cytokine CSBF inhibits both individual and synergistic proinflammatory signaling induced by IL-17A and TNF-α (IL-17A/TNF-α) in keratinocytes, playing a protective role in psoriatic inflammation. The expression of CSBF was increased in the skin lesions and serum of psoriatic patients, and IL-17A/TNF-α enhanced its production. Csbf deletion exacerbated IMQ-induced psoriasis-like skin inflammation and led to hyperactivation of IL-17A/TNF-α signaling in keratinocytes. The CSBF protein significantly ameliorated psoriatic manifestations and suppressed IL-17A/TNF-α signaling through the receptor SUSD2. Mechanistically, CSBF-SUSD2 competed with TRAF6 and TNFR1 for interaction with ACT1, inhibiting the IL-17A/TNF-α signaling pathway. Overall, the anti-inflammatory cytokine CSBF has the potential to be a therapeutic option for psoriasis by targeting keratinocytes.

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Data availability

The raw scRNA-seq data reported in this paper have been deposited in the Genome Sequence Archive (GSA) at the National Genomics Data Center, China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, and are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human under the accession number HRA006747. The raw MS data have been deposited in OMIX (https://ngdc.cncb.ac.cn/omix: accession no. OMIX005869) [58]. Published datasets reanalyzed in this study are available under accession codes GSE150672 [29] and GSE193350 [30]. This paper does not report the original code. All other data associated with this study are presented in the main text or the supplementary materials.

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Acknowledgements

We thank Prof. Dalong Ma (Peking University) for providing advice. We thank Prof. Peter Draber (Charles University) for sharing the 6 × His-2 × Strep-Flag-IL17A plasmid. This work was supported by grants from the Beijing Municipal Natural Science Foundation (No. 7232095) and the National Natural Science Foundation of China (Nos. 82171750, 82150104, 82203938, 82030095, and 82071850).

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  1. These authors contributed equally: Xixi Li, Kai Zhang.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center; NHC Key Laboratory of Medical Immunology, Beijing, China

    Xixi Li, Kai Zhang, Xiulan Yang, Yingying Cheng, Sihua Huang, Yuzhe Hu, Ting Li, Xiaoning Mo, Pingzhang Wang & Wenling Han

  2. Peking University Center for Human Disease Genomics, Beijing, China

    Xixi Li, Kai Zhang, Xiulan Yang, Yingying Cheng, Sihua Huang, Yuzhe Hu, Ting Li, Xiaoning Mo, Ruoyu Li, Pingzhang Wang & Wenling Han

  3. Department of Dermatology and Venerology, Peking University First Hospital, Peking University; National Clinical Research Center for Skin and Immune Diseases; Beijing Key Laboratory of Molecular Diagnosis of Dermatoses, Peking University, Beijing, China

    Kai Zhang, Weiwei Deng & Ruoyu Li

  4. Institute of Advanced Clinical Medicine, Peking University, Beijing, China

    Kai Zhang

  5. The Affiliated Hospital of Guizhou Medical University, Guizhou, China

    Xiulan Yang

  6. Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

    Yingying Cheng

  7. Dermatology Hospital of Southern Medical University, Guangzhou, China

    Weiwei Deng

  8. Department of Ophthalmology, Peking University Third Hospital; Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China

    Hongyu Duan

  9. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    Jianrui Zhang

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Contributions

WH, PW, RL, XL, KZ, and TL designed the study; XL, KZ, XY, and YC carried out the experiments and performed the data analysis; SH, YH, HD, TL, WD, XM, and JZ helped with the experiments and manuscript writing; PW and YH helped with the bioinformatics analysis; RL and KZ provided samples of patients; XL wrote the manuscript; WH, PW, RL, KZ and SH revised the manuscript; and WH, PW and RL supervised the study. All the authors have read and approved the article.

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Correspondence to Ruoyu Li, Pingzhang Wang or Wenling Han.

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Li, X., Zhang, K., Yang, X. et al. The cytokine CSBF inhibits the IL-17A and TNF-α inflammatory pathways via SUSD2-ACT1 in keratinocytes and alleviates IMQ-induced psoriasis. Cell Mol Immunol 22, 1109–1122 (2025). https://doi.org/10.1038/s41423-025-01325-3

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