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<p>IL-17A is a cytokine critical for tissue repair, but in excess, it prolongs inflammation and impairs healing. In type 2 diabetic (T2D) wounds, keratinocyte functions, including migration and inflammation, are disrupted, though mechanisms remain unclear. Here, we demonstrate that IL-17A regulates keratinocyte dysfunction via induction of the histone demethylase Jumonji domain-containing protein 3 (JMJD3) through a TRAF6/NFκB pathway. JMJD3 removes repressive histone 3 lysine 27 (H3K27me3) marks at anti-migratory (<i>Itga3, Timp1</i>) and inflammatory (<i>Ccl20, Cxcl1, Cxcl3, Cxcl5</i>) gene promoters, increasing transcription. Human and murine diabetic wounds exhibit elevated IL-17A signaling, JMJD3, and expression of associated anti-migratory and inflammatory genes compared to controls. Importantly, keratinocyte-specific deletion of IL-17A signaling or JMJD3 in diabetic mice improves wound healing and decreases expression of JMJD3 target genes. These findings reveal an IL-17A/JMJD3-mediated mechanism driving keratinocyte dysfunction in T2D wounds and highlight the therapeutic potential of targeting this axis to enhance wound repair.</p>

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IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Jadie Y. Moon,
  • Sonya J. Wolf,
  • Amrita D. Joshi,
  • He Zhang,
  • James Shadiow,
  • Tyler M. Bauer,
  • Kevin D. Mangum,
  • Lindsey D. Hughes,
  • Christopher O. Audu,
  • William J. Melvin,
  • Emily C. Barrett,
  • Sabrina Rocco,
  • Gabriela Saldana de Jimenez,
  • Amber L. Estor,
  • Moses Nelapudi,
  • Qinmengge Li,
  • Rachael Bogle,
  • Benjamin Levi,
  • Frank M. Davis,
  • Andrea T. Obi,
  • Bethany B. Moore,
  • Lam C. Tsoi,
  • Johann E. Gudjonsson,
  • Katherine A. Gallagher

摘要

IL-17A is a cytokine critical for tissue repair, but in excess, it prolongs inflammation and impairs healing. In type 2 diabetic (T2D) wounds, keratinocyte functions, including migration and inflammation, are disrupted, though mechanisms remain unclear. Here, we demonstrate that IL-17A regulates keratinocyte dysfunction via induction of the histone demethylase Jumonji domain-containing protein 3 (JMJD3) through a TRAF6/NFκB pathway. JMJD3 removes repressive histone 3 lysine 27 (H3K27me3) marks at anti-migratory (Itga3, Timp1) and inflammatory (Ccl20, Cxcl1, Cxcl3, Cxcl5) gene promoters, increasing transcription. Human and murine diabetic wounds exhibit elevated IL-17A signaling, JMJD3, and expression of associated anti-migratory and inflammatory genes compared to controls. Importantly, keratinocyte-specific deletion of IL-17A signaling or JMJD3 in diabetic mice improves wound healing and decreases expression of JMJD3 target genes. These findings reveal an IL-17A/JMJD3-mediated mechanism driving keratinocyte dysfunction in T2D wounds and highlight the therapeutic potential of targeting this axis to enhance wound repair.