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<p>The pathogenesis of autoimmune diseases remains poorly understood, largely because existing models fail to capture both the initial triggers and the full spectrum of systemic manifestations. Here, we identify the skin epithelium as an initiating site of autoimmune activation. Specifically, we found that PPARγ levels are broadly reduced in basal-layer keratinocytes from patients across the lupus disease spectrum. To investigate the functional impact of this epithelial defect, we employed keratinocyte-specific gene editing in mice. Localized editing induced cutaneous lupus-like inflammation, while more extensive epithelial perturbation triggered rapid systemic autoimmunity, characterized by multi-organ inflammation and autoantibody production. Moreover, ultraviolet exposure accelerated the progression from cutaneous to systemic disease, recapitulating the spectrum transition and clinical photosensitivity. Mechanistically, we found that proinflammatory keratinocytes promoted the emergence of migratory CCR7⁺ dendritic cells, which appeared to initiate and amplify immune activation beyond the epithelial niche. Our findings establish the skin epithelium as a critical initiator of autoimmunity and provide a tunable model that recapitulates key features of human lupus spectrum.</p>

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Proinflammatory keratinocytes drive a novel mouse model of autoimmunity with systemic and cutaneous lupus erythematosus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Jingru Tian,
  • Liqing Shi,
  • Dingyao Zhang,
  • Xu Yao,
  • Jun Lu,
  • Ming Zhao,
  • Qianjin Lu

摘要

The pathogenesis of autoimmune diseases remains poorly understood, largely because existing models fail to capture both the initial triggers and the full spectrum of systemic manifestations. Here, we identify the skin epithelium as an initiating site of autoimmune activation. Specifically, we found that PPARγ levels are broadly reduced in basal-layer keratinocytes from patients across the lupus disease spectrum. To investigate the functional impact of this epithelial defect, we employed keratinocyte-specific gene editing in mice. Localized editing induced cutaneous lupus-like inflammation, while more extensive epithelial perturbation triggered rapid systemic autoimmunity, characterized by multi-organ inflammation and autoantibody production. Moreover, ultraviolet exposure accelerated the progression from cutaneous to systemic disease, recapitulating the spectrum transition and clinical photosensitivity. Mechanistically, we found that proinflammatory keratinocytes promoted the emergence of migratory CCR7⁺ dendritic cells, which appeared to initiate and amplify immune activation beyond the epithelial niche. Our findings establish the skin epithelium as a critical initiator of autoimmunity and provide a tunable model that recapitulates key features of human lupus spectrum.