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

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

doi:10.1038/s41467-025-67456-3

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

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^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English
Article number	780
Pages (from-to)	780
Journal	Nature Communications
Volume	17
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-67456-3
State	Published - 18 Dec 2025

Keywords

Animals
Cell Movement
Diabetes Mellitus, Experimental/metabolism
Diabetes Mellitus, Type 2/metabolism
Female
Humans
Inflammation
Interleukin-17/metabolism
Jumonji Domain-Containing Histone Demethylases/metabolism
Keratinocytes/metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B/metabolism
Signal Transduction
Wound Healing/genetics

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10.1038/s41467-025-67456-3

Cite this

Moon, J. Y., Wolf, S. J., Joshi, A. D., Zhang, H., Shadiow, J., Bauer, T. M., Mangum, K. D., Hughes, L. D., Audu, C. O., Melvin, W. J., Barrett, E. C., Rocco, S., de Jimenez, G. S., Estor, A. L., Nelapudi, M., Li, Q., Bogle, R., Levi, B., Davis, F. M., ... Gallagher, K. A. (2025). IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3. Nature Communications, 17(1), 780. Article 780. https://doi.org/10.1038/s41467-025-67456-3

@article{9e9f96fae7f84b61b1ee2fdc8455cfdd,

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

abstract = "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.",

keywords = "Animals, Cell Movement, Diabetes Mellitus, Experimental/metabolism, Diabetes Mellitus, Type 2/metabolism, Female, Humans, Inflammation, Interleukin-17/metabolism, Jumonji Domain-Containing Histone Demethylases/metabolism, Keratinocytes/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B/metabolism, Signal Transduction, Wound Healing/genetics",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

day = "18",

doi = "10.1038/s41467-025-67456-3",

language = "English",

volume = "17",

pages = "780",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Moon, JY, Wolf, SJ, Joshi, AD, Zhang, H, Shadiow, J, Bauer, TM, Mangum, KD, Hughes, LD, Audu, CO, Melvin, WJ, Barrett, EC, Rocco, S, de Jimenez, GS, Estor, AL, Nelapudi, M, Li, Q, Bogle, R, Levi, B, Davis, FM, Obi, AT, Moore, BB, Tsoi, LC, Gudjonsson, JE & Gallagher, KA 2025, 'IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3', Nature Communications, vol. 17, no. 1, 780, pp. 780. https://doi.org/10.1038/s41467-025-67456-3

TY - JOUR

T1 - IL-17A is increased in diabetic wounds and impairs keratinocyte function via histone demethylase JMJD3

AU - Moon, Jadie Y.

AU - Wolf, Sonya J.

AU - Joshi, Amrita D.

AU - Zhang, He

AU - Shadiow, James

AU - Bauer, Tyler M.

AU - Mangum, Kevin D.

AU - Hughes, Lindsey D.

AU - Audu, Christopher O.

AU - Melvin, William J.

AU - Barrett, Emily C.

AU - Rocco, Sabrina

AU - de Jimenez, Gabriela Saldana

AU - Estor, Amber L.

AU - Nelapudi, Moses

AU - Li, Qinmengge

AU - Bogle, Rachael

AU - Levi, Benjamin

AU - Davis, Frank M.

AU - Obi, Andrea T.

AU - Moore, Bethany B.

AU - Tsoi, Lam C.

AU - Gudjonsson, Johann E.

AU - Gallagher, Katherine A.

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/12/18

Y1 - 2025/12/18

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Movement

KW - Diabetes Mellitus, Experimental/metabolism

KW - Diabetes Mellitus, Type 2/metabolism

KW - Female

KW - Humans

KW - Inflammation

KW - Interleukin-17/metabolism

KW - Jumonji Domain-Containing Histone Demethylases/metabolism

KW - Keratinocytes/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - NF-kappa B/metabolism

KW - Signal Transduction

KW - Wound Healing/genetics

UR - https://www.scopus.com/pages/publications/105028254659

U2 - 10.1038/s41467-025-67456-3

DO - 10.1038/s41467-025-67456-3

M3 - Article

C2 - 41413388

AN - SCOPUS:105028254659

SN - 2041-1723

VL - 17

SP - 780

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 780

ER -

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

Abstract

Keywords

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