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<p>Atopic dermatitis (AD) is a common chronic inflammatory skin disease with heterogeneous and poorly understood mechanisms. We perform single-cell RNA sequencing of lesional (LAD) and non-lesional (NAD) skin from 42 AD patients and 23 healthy controls (HC). Keratinocytes (KCs) are the predominant disease-relevant cell type. In healthy skin, KC differentiation follows a linear trajectory from basal KCs through seven differentiated stages to terminal keratinized cells. In LAD, this process is disrupted, showing a reversed terminal transition mainly driven by DK7 cells. <i>APOD</i>, <i>LYZ</i> and <i>SERPINB4</i> emerge as LAD-specific regulators linked to IL-13/IL-22 responses, ER stress and oxidative damage. Mitochondrial and ER dysfunction are specifically enriched in LAD DK6 cells, indicating a key pathogenic compartment. Spatial transcriptomics and cell-cell interaction analysis further identify LAD-specific TWEAK signaling from IL-13<sup><i>+</i></sup> Th2/cycling T cells to Fn14<sup>+</sup> basal/differentiated KCs. Here, we reveal disrupted KC differentiation and immune signaling circuits in AD, highlighting potential therapeutic targets.</p>

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Single-cell transcriptome reveals keratinocyte subclusters contributing to altered differentiation and inflammatory responses in atopic dermatitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Tingting Qin,
  • Rachael Bogle,
  • Rundong Jiang,
  • Mrinal K. Sarkar,
  • Yuli Cai,
  • Mehrnaz Gharaee-Kermani,
  • Jennifer Fox,
  • Xianying Xing,
  • Sahiti Marella,
  • Mio Nakamura,
  • Emanual Maverakis,
  • Stephanie T. Le,
  • Alexander A. Merleev,
  • Alina I. Marusina,
  • Cory L. Simpson,
  • Arti Parihar,
  • Connor Hill,
  • He Li,
  • J. Michelle Kahlenberg,
  • Dawn M. Waterworth,
  • Nina Sabins,
  • Lloyd S. Miller,
  • Tom C. Freeman,
  • Monica WL Leung,
  • Marta E. Polak,
  • Lam C. Tsoi,
  • Allison C. Billi,
  • Johann E. Gudjonsson

摘要

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with heterogeneous and poorly understood mechanisms. We perform single-cell RNA sequencing of lesional (LAD) and non-lesional (NAD) skin from 42 AD patients and 23 healthy controls (HC). Keratinocytes (KCs) are the predominant disease-relevant cell type. In healthy skin, KC differentiation follows a linear trajectory from basal KCs through seven differentiated stages to terminal keratinized cells. In LAD, this process is disrupted, showing a reversed terminal transition mainly driven by DK7 cells. APOD, LYZ and SERPINB4 emerge as LAD-specific regulators linked to IL-13/IL-22 responses, ER stress and oxidative damage. Mitochondrial and ER dysfunction are specifically enriched in LAD DK6 cells, indicating a key pathogenic compartment. Spatial transcriptomics and cell-cell interaction analysis further identify LAD-specific TWEAK signaling from IL-13+ Th2/cycling T cells to Fn14+ basal/differentiated KCs. Here, we reveal disrupted KC differentiation and immune signaling circuits in AD, highlighting potential therapeutic targets.