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  3. Dysregulation in keratinocytes drives systemic lupus erythematosus onset

Dysregulation in keratinocytes drives systemic lupus erythematosus onset

  • Cell Mol Immunol. 2025 Jan;22(1):83-96. doi: 10.1038/s41423-024-01240-z.
Jingru Tian # 1 2 3 4,  Liqing Shi # 1 2 3,  Dingyao Zhang 5,  Xu Yao 1 4,  Ming Zhao 1 2 3,  Snehlata Kumari 6 7,  Jun Lu 8 9 10 11 12,  Di Yu 6 13 14,  Qianjin Lu 15 16 17
Affiliations

Affiliations

  • 1 Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
  • 2 Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
  • 3 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
  • 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.
  • 5 Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
  • 6 Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia.
  • 7 Translational Research Institute, Brisbane, QLD, Australia.
  • 8 Yale Stem Cell Center, New Haven, CT, USA.
  • 9 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • 10 Yale Cancer Center, New Haven, CT, USA.
  • 11 Yale Center for RNA Science and Medicine, New Haven, CT, USA.
  • 12 Yale Cooperative Center of Excellence in Hematology, New Haven, CT, USA.
  • 13 John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • 14 Faculty of Medicine, Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia.
  • 15 Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. qianlu5860@pumcderm.cams.cn.
  • 16 Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China. qianlu5860@pumcderm.cams.cn.
  • 17 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China. qianlu5860@pumcderm.cams.cn.
  • # Contributed equally.
PMID: 39627610 DOI: 10.1038/s41423-024-01240-z
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.

Keywords

Dendritic cells; Interferon regulatory factor 3; Keratinocytes; Peroxisome proliferator-activated receptor gamma; Systemic lupus erythematosus; Type I interferon.

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