IFN-κ is critical for normal wound repair and is decreased in diabetic wounds
Sonya J. Wolf, … , J. Michelle Kahlenberg, Katherine A. Gallagher
Sonya J. Wolf, … , J. Michelle Kahlenberg, Katherine A. Gallagher
Published March 31, 2022
Citation Information: JCI Insight. 2022;7(9):e152765. https://doi.org/10.1172/jci.insight.152765.
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Research Article Inflammation

IFN-κ is critical for normal wound repair and is decreased in diabetic wounds

Abstract

Wound repair following acute injury requires a coordinated inflammatory response. Type I IFN signaling is important for regulating the inflammatory response after skin injury. IFN-κ, a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFN-κ in the context of normal or dysregulated wound healing is unclear. Here, we show that Ifnk expression is upregulated in keratinocytes early after injury and is essential for normal tissue repair. Under diabetic conditions, IFN-κ was decreased in wound keratinocytes, and early inflammation was impaired. Furthermore, we found that the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is upregulated early following injury and regulates Ifnk expression in diabetic wound keratinocytes via an H3K4me3-mediated mechanism. Using a series of in vivo studies with a geneticall y engineered mouse model (Mll1fl/fl K14cre–) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte–mediated Ifnk expression and that Mll1 expression is decreased in T2D keratinocytes. Importantly, we found the administration of IFN-κ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and reepithelialization. These findings have significant implications for understanding the complex role type I IFNs play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest that IFN may be a viable therapeutic target to improve diabetic wound repair.

Authors

Sonya J. Wolf, Christopher O. Audu, Amrita Joshi, Aaron denDekker, William J. Melvin, Frank M. Davis, Xianying Xing, Rachael Wasikowski, Lam C. Tsoi, Steven L. Kunkel, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg, Katherine A. Gallagher

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Figure 4

IFN-κ expression in diabetic keratinocytes is regulated by MLL1.

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IFN-κ expression in diabetic keratinocytes is regulated by MLL1. (A) Wou...
(A) Wound keratinocytes were isolated from day 0, 1, 3, and 5 wounds. Mll1 expression was examined via qPCR. n = 3 mice per group repeated 2 times in triplicate. (B and C) Keratinocytes at baseline and wounds were isolated from ND and DIO mice. Mll1 gene expression was measured via qPCR (n = 4 mice per group, repeated in triplicate). (D and E) Keratinocytes at baseline and wounds were isolated from DIO and control mice. ChIP analysis for H3K4me3 deposition at the Ifnk promoter was performed in keratinocytes from wounds and at baseline of DIO and control mice (n = 3 per group, repeated in triplicate). Respective IgG controls (dotted line). (F) Keratinocytes were isolated from DIO and control wounds. ChIP analysis for MLL1 deposition at the Ifnk promoter was performed (n = 3 per group, repeated in triplicate). The dotted line indicates the respective IgG controls. (G) Keratinocytes were isolated from Mll1fl/fl K14cre+ and littermate controls and analyzed for Ifnk expression by qPCR (n = 3 mice per group, repeated in triplicate). (H) The 4 mm punch biopsy wounds were created on Mll1fl/fl K14cre+ and littermate controls. The change in wound area was analyzed with ImageJ software (2 wounds per mouse, n = 4–5 mice per group). (I) Wounds isolated from Mll1fl/fl K14cre+ and control mice on day 3; n = 3 per group. Gene expression of inflammatory cytokines Tnf and Il1b were measured via qPCR. Data were analyzed for variances, and 2-tailed Student’s t test or 1-way ANOVA was performed. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Data are presented as mean ± SEM.