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Dysregulation in keratinocytes drives systemic lupus erythematosus onset

Cellular & Molecular Immunology volume 22, pages 83–96 (2025)Cite this article

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A Comment to this article was published on 17 January 2025

Abstract

Systemic lupus erythematosus (SLE) is a complex, multiorgan autoimmune disorder. Although it is widely believed that SLE originates from immune cell dysregulation, the etiology of SLE is not yet clear. Here, we propose a new theory in which SLE can be directly initiated by molecular alterations in keratinocytes rather than immune cells. We found that the level of peroxisome proliferator-activated receptor gamma (PPARγ) is substantially reduced in the skin lesions of patients, and replicating this reduction in mice led to rapid disease onset with multiple hallmarks of SLE. As PPARγ decreases in keratinocytes, which is accompanied by increased occupancy of interferon regulatory factor 3 at the type I interferon locus, dendritic cells (DCs) are recruited to the epidermis and are activated by keratinocyte-secreted type I interferon. These activated DCs migrate to local draining lymph nodes, where they activate CD4+ T cells in a non-MHC II-dependent manner, promoting their differentiation into effector T cells and thus contributing to disease onset. Our study revealed that the dysregulation of keratinocytes can be a pathogenic driver of SLE and describes a new mouse model that mimics human SLE. Our data also emphasize the pivotal role of skin immunity in the onset of systemic autoimmune disease.

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Funding

The CAMS Innovation Fund for Medical Sciences grant No. 2021-I2M-1-059. Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences grant Nos. 2021-RC320-001 and 2020-RC320-003. National Natural Science Foundation of China grant No. 81830097 and No. 82203933. the Special Program of the National Natural Science Foundation of China grant No. 32141004.

Author information

Author notes

  1. These authors contributed equally: Jingru Tian, Liqing Shi.

Authors and Affiliations

  1. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China

    Jingru Tian, Liqing Shi, Xu Yao, Ming Zhao & Qianjin Lu

  2. Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China

    Jingru Tian, Liqing Shi, Ming Zhao & Qianjin Lu

  3. Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China

    Jingru Tian, Liqing Shi, Ming Zhao & Qianjin Lu

  4. Department of Allergy and Rheumatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China

    Jingru Tian & Xu Yao

  5. Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA

    Dingyao Zhang

  6. Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia

    Snehlata Kumari & Di Yu

  7. Translational Research Institute, Brisbane, QLD, Australia

    Snehlata Kumari

  8. Yale Stem Cell Center, New Haven, CT, USA

    Jun Lu

  9. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    Jun Lu

  10. Yale Cancer Center, New Haven, CT, USA

    Jun Lu

  11. Yale Center for RNA Science and Medicine, New Haven, CT, USA

    Jun Lu

  12. Yale Cooperative Center of Excellence in Hematology, New Haven, CT, USA

    Jun Lu

  13. John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

    Di Yu

  14. Faculty of Medicine, Ian Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia

    Di Yu

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  1. Jingru Tian
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Contributions

Conceptualization: JT, QL. Methodology: JT, DZ. Visualization: JT, LS, DZ. Funding acquisition: QL. Project administration: QL. Supervision: JT, QL. Writing – original draft: JT, LS. Writing – review & editing: LS, XY, JL, MZ, SK, and DY.

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Correspondence to Qianjin Lu.

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The authors declare that they have no competing interests. QL and DY are editorial board members of Cellular & Molecular Immunology, but they have not been involved in the peer review or the decision-making of the article.

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Tian, J., Shi, L., Zhang, D. et al. Dysregulation in keratinocytes drives systemic lupus erythematosus onset. Cell Mol Immunol 22, 83–96 (2025). https://doi.org/10.1038/s41423-024-01240-z

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