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

Résumé fourni par la source

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. IL-17A, a cytokine important for tissue repair, can impair healing when increased, contributing to keratinocyte dysfunction in type 2 diabetic wounds. Here, the authors show that IL-17A drives this dysfunction via JMJD3-mediated epigenetic changes, and that blocking this pathway improves wound healing.

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