TNF-α represses fibroblast to myofibroblast transition through the histone methyltransferase Setdb2

Fibroblast to myofibroblast transition is a critical event required for effective tissue repair. In pathologic wound repair processes, such as type 2 diabetes (T2D), fibroblast to myofibroblast transition is impaired. The exact factors that control this transition in wounds are unclear. Here, using human tissue and murine transgenic models, we show that the histone methyltransferase SETDB2 is elevated in diabetic wound fibroblasts and TNF-α represses fibroblast to myofibroblast transition via Setdb2. We identified that TNF-α increases Setdb2 in fibroblasts via a JAK1,3/STAT3 signaling pathway, where pharmacologic or genetic manipulation of this pathway altered Setdb2 in fibroblasts. We also found that fibroblasts treated with pro-inflammatory macrophage supernatants displayed increased Setdb2 and downregulated myofibroblast genes; inhibition of the TNF-α receptor reduced the upregulation of Setdb2. In diabetes, we showed that TNF-α signaling was increased in wound fibroblasts, which functions to increase Setdb2 expression and represses fibroblast to myofibroblast transition. Fibroblast-specific knockdown of SETDB2 and therapeutic inhibition of JAK1,3/STAT3 improved diabetic wound repair, where wound fibroblasts expressed increased myofibroblast genes. This study is the first to our knowledge to identify an epigenetic mechanism for reduced fibroblast to myofibroblast transition in diabetic wounds. Therapeutic targeting of the TNF-α/STAT3/SETDB2 axis in wound fibroblasts may improve diabetic wound healing.