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<p>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 <i>Ube2l3</i> conditional knockout mouse skin in the epidermis rather than dermis. IL-17A is regulated by CXCR6<sup>+</sup> Vγ2<sup>+</sup> γδT cells in mouse while CXCR6<sup>+</sup> CD8<sup>+</sup> T cells in human. CXCL16 is the only chemokine that binds to and stimulates CXCR6. <i>Ube2l3</i> 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<sup>+</sup> γδT17 or CD8<sup>+</sup> 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<sup>+</sup> γδT cells in mouse and CD8<sup>+</sup> T cells in human through the CXCL16/CXCR6 signaling pathway in psoriasis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月13日

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  • 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,
  • Xiao-Yong Man

摘要

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.