Interferon kappa (IFNk) in keratinocytes is critical for normal wound repair and is decreased in diabetic wounds
JOURNAL OF IMMUNOLOGY(2022)
摘要
Abstract Wound repair following acute injury requires a coordinated inflammatory response. Type I interferon (IFN) signaling is important for regulating the inflammatory response post- skin injury. IFN kappa (IFNk), a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFNk in the context of normal or dysregulated wound healing is unclear. Thus, this project explores the role of IFNk in wound repair. Here, we found that IFNk expression is upregulated in keratinocytes early post-injury and is essential for normal tissue repair. Under diabetic conditions, IFNk was decreased in wound keratinocytes, and early inflammation was impaired. Further, we found that the histone methyltransferase mixed lineage leukemia protein-1(MLL1) regulates IFNk expression in diabetic wound keratinocytes via an H3K4me3 mediated mechanism. Using a series of in vivo studies with a genetically engineered mouse model(Mll1fl/flK14cre−) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated IFNk and MLL1 is decreased in T2D keratinocytes. Importantly, we find the administration of IFNk early following injury improves diabetic tissue repair. These findings have significant implications for understanding the complex role type I interferons play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest IFNk may be a viable therapeutic target to improve diabetic wound repair. Supported by MNORC P30-DK089503
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关键词
keratinocytes,normal wound repair,interferon,wounds,diabetic
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