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ResearchIn-Press PreviewDermatologyImmunology Open Access | 10.1172/JCI186135

CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling

Fan Xu,1 Ying-Zhe Cui,2 Xing-Yu Yang,2 Yu-Xin Zheng,2 Xi-Bei Chen,2 Hao Zhou,3 Zhao-Yuan Wang,2 Yuan Zhou,2 Yi Lu,4 Ying-Ying Li,2 Li-Ran Ye,2 Ni-Chang Fu,2 Si-Qi Chen,2 Xue-Yan Chen,2 Min Zheng,2 Yong Yang,5 and Xiao-Yong Man2

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Xu, F. in: PubMed | Google Scholar |

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Cui, Y. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Yang, X. in: PubMed | Google Scholar |

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zheng, Y. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Chen, X. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhou, H. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Wang, Z. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhou, Y. in: PubMed | Google Scholar |

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Lu, Y. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Li, Y. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Ye, L. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Fu, N. in: PubMed | Google Scholar |

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Chen, S. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Chen, X. in: PubMed | Google Scholar |

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zheng, M. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Yang, Y. in: PubMed | Google Scholar

1Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine Dermatology, Hangzhou, China

2Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

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

4Department of Dermatology of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

5Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Man, X. in: PubMed | Google Scholar

Published June 5, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186135.
Copyright © 2025, Xu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 5, 2025 - Version history
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Abstract

Psoriatic arthritis (PsA) is a multifaceted chronic inflammatory disease affecting the skin, joints, and entheses, and is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement, however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermal-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2-STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF𝜶 production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1-CXCL10-periarticular CD14hi macrophages-TNFα axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.

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