The histone methyltransferase SETDB2 modulates keratinocyte inflammatory phenotype in diabetic wound repair via an IFNβ/JAK/STAT mechanism 2142

Abstract Description Diabetic keratinocytes overexpress inflammatory cytokines, contributing to prolonged inflammation and impaired healing. Using diet-induced obese (DIO) and db/db murine models of type 2 diabetes (T2D) and single-cell sequencing of human wound tissue from T2D patients, we found that the repressive histone methyltransferase SETDB2 is decreased in diabetic wound keratinocytes. The effects of decreased SETDB2 on keratinocyte function and its upstream signaling remain unclear. Chromatin immunoprecipitation revealed that decreased SETDB2 in diabetic keratinocytes results in increased inflammatory gene expression, namely TNFα, due to decreased H3K9me3 marks at the Tnfα promoter. To identify the upstream regulators of SETDB2, bulk RNA-seq analysis showed decreased interferon signaling in diabetic (db/db) keratinocytes. Stimulating keratinocytes with IFNβ (20 U/mL) increased Setdb2, while treatment with the JAK inhibitor tofacitinib decreased Setdb2. Using keratinocytes from Ifnar-/- and Stat1-/- mice, we confirmed that Setdb2 is mediated by IFNβ through the JAK/STAT pathway. Lastly, subcutaneous injections of IFNβ (0.25 μg) in DIO mice improved wound healing rates. These findings suggest that activating the IFNβ/JAK/STAT1 pathway may offer a therapeutic approach to enhance diabetic wound repair. Further investigation into the upstream signaling in keratinocytes and its impact on keratinocyte-immune cell crosstalk may reveal new therapeutic targets for improving diabetic wound healing. Funding Sources F31-DK136199 (JYM), T32-AI007413 (BBM), R01-HL137919 (KAG), R01-DK124290 (KAG), R01-HL15627401 (KAG), R01-DK127531 (KAG) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)