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 6

Administration of IFN-κ improves diabetic wound healing.

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Administration of IFN-κ improves diabetic wound healing. (A) The 4 mm pu...
(A) The 4 mm punch biopsy wounds were created on DIO, and wounds were injected daily starting on day 0 for 3 days after injury with IFN-κ (0.5 μg/100 μL) or PBS control (2 wounds per mouse, n = 5 mice per group, repeated once). The arrow indicates when injections started. The change in wound area was recorded daily and analyzed with ImageJ software. Representative photographs of the wounds were taken on days 0 and 3. (B) Max wound diameter at day 3 for IFN-κ and PBS control; n = 5 per group. Trichrome staining representative picture. (C) Trichrome staining was calculated using ImageJ software (n = 5 mice/group). (D) The 4 mm punch biopsy wounds were created and splinted on DIO mice, and wounds were injected starting on day 0 for 3 days after injury with IFN-κ (0.5 μg/100 μL) or PBS control (1 wound per mouse, n = 7–8 mice per group). The arrow indicates when injections started. The change in wound area was recorded daily and analyzed with ImageJ software. Representative photographs of the wounds were taken on days 0, 3, and 5. (E) Flow cytometry quantification of Ly6Chi cells in wounds (n = 7–8 per group). (F) Wound monocyte/macrophages (MΦ) (CD3–CD19–NK1.1–Ly6G–CD11b+) were isolated from IFN-κ or PBS control mice on day 3; n = 3 per group, repeated in triplicate. Gene expression of inflammatory cytokines Tnf, Il1b, and Il12 was 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, and **** P < 0.0001. Data are presented as mean ± SEM.