IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3
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.
Authors
- Katherine Ann Gallagher (ORCID: https://orcid.org/0000-0002-8791-6980)
- Kevin Mangum (ORCID: https://orcid.org/0000-0003-2838-7094)
- Sonya Wolf (ORCID: https://orcid.org/0000-0003-3626-9274)
- James Shadiow (ORCID: https://orcid.org/0000-0003-0293-6753)
- Christopher O. Audu (ORCID: https://orcid.org/0000-0002-4183-8825)
- Bethany B. Moore (ORCID: https://orcid.org/0000-0003-3051-745X)
- Qinmengge Li
- Benjamin Lévi (ORCID: https://orcid.org/0000-0001-8272-7139)
- Emily Barrett
- Lindsey D. Hughes (ORCID: https://orcid.org/0000-0002-1764-4553)
- William J. Melvin (ORCID: https://orcid.org/0000-0002-3241-5919)
- Frank M. Davis (ORCID: https://orcid.org/0000-0002-5847-8993)
- Lam C. Tsoi (ORCID: https://orcid.org/0000-0003-1627-5722)
- Johann Eli Gudjonsson (ORCID: https://orcid.org/0000-0002-0080-0812)
- Tyler M. Bauer (ORCID: https://orcid.org/0000-0002-5430-5104)
- Amrita Joshi (ORCID: https://orcid.org/0000-0001-6936-7132)
- Sabrina Rocco (ORCID: https://orcid.org/0000-0002-7822-072X)
- Jadie Y. Moon (ORCID: https://orcid.org/0000-0001-9451-6806)
- Rachael Bogle (ORCID: https://orcid.org/0000-0003-3544-3023)
- Gabriela Saldana de Jimenez
- T. Andrea (ORCID: https://orcid.org/0000-0001-7613-2366)
- He Zhang (ORCID: https://orcid.org/0009-0001-1899-2402)
- Amber L Estor
- Moses Nelapudi
Institutions
- University of Michigan (US)
- Southwestern Medical Center (US)
- Michigan Medicine (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1038/s41467-025-67456-3
- Citations
- 1
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- article
- Field-Weighted Citation Impact
- 0.80