Nature communications · 2025
IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3.
СтатьяНазвание и аннотация: Перевод в очереди
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Moon Jadie Y, Wolf Sonya J, Joshi Amrita D, Zhang He, Shadiow James, Bauer Tyler M, Mangum Kevin D, Hughes Lindsey D, Audu Christopher O, Melvin William J, Barrett Emily C, Rocco Sabrina, de Jimenez Gabriela Saldana, Estor Amber L, Nelapudi Moses, Li Qinmengge, Bogle Rachael, Levi Benjamin, Davis Frank M, Obi Andrea T, Moore Bethany B, Tsoi Lam C, Gudjonsson Johann E, Gallagher Katherine A
Аннотация
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.