Single cell transcriptomics of human psoriasis and epidermal specific Ube2l3 deficient mice highlight CXCL16/CXCR6 involvement in psoriasis development

Xue-Yan Chen, Li-Ran Ye, Ni-Chang Fu, Si-Qi Chen, Bing-Xi Yan, Yu-Xin Zheng, Xi-Bei Chen, Yuan Zhou, Ming-Yue Lv, Ying-Zhe Cui, Fan Xu, Min Zheng and Xiao-Yong Man ()
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Xue-Yan Chen: Zhejiang University School of Medicine
Li-Ran Ye: Zhejiang University School of Medicine
Ni-Chang Fu: Zhejiang University School of Medicine
Si-Qi Chen: Zhejiang University School of Medicine
Bing-Xi Yan: Zhejiang University School of Medicine
Yu-Xin Zheng: Zhejiang University School of Medicine
Xi-Bei Chen: Zhejiang University School of Medicine
Yuan Zhou: Zhejiang University School of Medicine
Ming-Yue Lv: Zhejiang University School of Medicine
Ying-Zhe Cui: Zhejiang University School of Medicine
Fan Xu: Zhejiang University School of Medicine
Min Zheng: Zhejiang University School of Medicine
Xiao-Yong Man: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Psoriasis is a chronic, complex immune-mediated inflammatory disorder with cutaneous and systemic manifestations in which keratinocytes, dendritic cells and T cells have central roles. UBE2L3 may be a protective biomarker that regulates the pathogenesis of psoriasis. Here, we identify the IL-17A signaling similarity between human psoriatic skin and Ube2l3 conditional knockout mouse skin in the epidermis rather than dermis. IL-17A is regulated by CXCR6+ Vγ2+ γδT cells in mouse while CXCR6+ CD8+ T cells in human. CXCL16 is the only chemokine that binds to and stimulates CXCR6. Ube2l3 reduction in keratinocytes activates IL-1β and then promotes CXCL16 expression through STAT3 signaling. Up-regulated CXCL16 in keratinocytes and cDC2/mDC then attracts Vγ2+ γδT17 or CD8+ T cells to secrete IL-17A and form a positive feedback loop in keratinocytes supporting psoriatic lesions. Thus, UBE2L3 is a keratinocyte-intrinsic suppressor of epidermal IL-17 production in Vγ2+ γδT cells in mouse and CD8+ T cells in human through the CXCL16/CXCR6 signaling pathway in psoriasis.

Date: 2025
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DOI: 10.1038/s41467-025-64106-6

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