Nature communications · 2026
Single-cell transcriptome reveals keratinocyte subclusters contributing to altered differentiation and inflammatory responses in atopic dermatitis.
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Qin Tingting, Bogle Rachael, Jiang Rundong, Sarkar Mrinal K, Cai Yuli, Gharaee-Kermani Mehrnaz, Fox Jennifer, Xing Xianying, Marella Sahiti, Nakamura Mio, Maverakis Emanual, Le Stephanie T, Merleev Alexander A, Marusina Alina I, Simpson Cory L, Parihar Arti, Hill Connor, Li He, Kahlenberg J Michelle, Waterworth Dawn M, Sabins Nina, Miller Lloyd S, Freeman Tom C, Leung Monica Wl, Polak Marta E, Tsoi Lam C, Billi Allison C, Gudjonsson Johann E
Аннотация
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.