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<p>Chronic itch poses a significant clinical burden, with activation of the brain natriuretic peptide (BNP) pathway as a hallmark, though its transcriptional control remains unclear. We identify T-box transcription factor 20 (TBX20) as upregulated in skin of atopic dermatitis patients, with increased expression in NPR1<sup>+</sup> keratinocytes. ChIP peak calling, ChIP-qPCR and dual-luciferase assays show TBX20 activates the NPR1 promoter. In mice, keratinocyte-specific TBX20 knockout (TBX20<sup>fl/fl</sup>; K14-Cre) reduces scratching, IL-4 and Oncostatin M levels, basophil markers, and decreases cutaneous NPR1 expression. TBX20 is also expressed in a subset of NPR1<sup>+</sup> sensory neurons, and neuron-specific deletion similarly alleviates itch, basophil infiltration, and barrier dysfunction. RNA-seq identifies lipocalin-2 as a downstream effector of the TBX20-NPR1 axis, and its deletion reduces itch. Conversely, AAV-mediated TBX20 rescue exacerbates symptoms. Neuregulin 1 suppresses TBX20, attenuates IL-13-driven NPR1 signalling, and reduces itch. These findings define a TBX20-NPR1 axis as a critical regulator of chronic itch and skin dysfunction.</p>

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Misregulation of T-box transcription factors drives BNP–NPR1 signalling underlying chronic itch

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Xiaolong Dai,
  • Michael Kitching,
  • Wenke Cheng,
  • Rengang Luo,
  • Lianlian Li,
  • Renkai Zhu,
  • Chunxu Shan,
  • Weiwei Chen,
  • Timo Buhl,
  • Andrea Szegedi,
  • Jorg Buddenkotte,
  • Shouming Xu,
  • Jiafu Wang,
  • Jianghui Meng

摘要

Chronic itch poses a significant clinical burden, with activation of the brain natriuretic peptide (BNP) pathway as a hallmark, though its transcriptional control remains unclear. We identify T-box transcription factor 20 (TBX20) as upregulated in skin of atopic dermatitis patients, with increased expression in NPR1+ keratinocytes. ChIP peak calling, ChIP-qPCR and dual-luciferase assays show TBX20 activates the NPR1 promoter. In mice, keratinocyte-specific TBX20 knockout (TBX20fl/fl; K14-Cre) reduces scratching, IL-4 and Oncostatin M levels, basophil markers, and decreases cutaneous NPR1 expression. TBX20 is also expressed in a subset of NPR1+ sensory neurons, and neuron-specific deletion similarly alleviates itch, basophil infiltration, and barrier dysfunction. RNA-seq identifies lipocalin-2 as a downstream effector of the TBX20-NPR1 axis, and its deletion reduces itch. Conversely, AAV-mediated TBX20 rescue exacerbates symptoms. Neuregulin 1 suppresses TBX20, attenuates IL-13-driven NPR1 signalling, and reduces itch. These findings define a TBX20-NPR1 axis as a critical regulator of chronic itch and skin dysfunction.