Diabetic wound macrophage IL6 drives fibroblast dysfunction via the histone methyltransferase, SETDB2

Abstract

Abstract Interactions between innate immune cells and structural cells are vital to proper tissue repair and regeneration after injury. Under pathologic conditions such as type 2 diabetes (T2D), Mϕs exist in a chronic inflammatory state that drives dysregulated wound repair, in part by altering the fibroblast response to injury. We have previously shown that wound Mϕs from a murine model that mimics T2D (diet-induced obese mice; DIO) physiology, display increased levels of inflammatory cytokines, including IL6. Here, we found that rIL6 drives CD202-, CD45-, CD31-, Epcam-, TER119-fibroblasts isolated from wounds to produce decreased levels of col1A and periostin, two mediators that are crucial for fibroblast function in wound repair. Although the underlying mechanisms remain unclear, we and others have shown that both immune and structural cell functions in tissues can be controlled by epigenetic modifications that alter gene expression. Using our human single cell sequencing data from T2D wounds we identified that the histone methyltransferase, SETDB2, was increased in T2D fibroblasts, compared to non-wounded controls. We then isolated fibroblasts from wounds and stimulated them with rIL6 and identified an increase in H3K9me3, the histone methylation mark specific for SETDB2, at the promoters of the col1A and periostin genes. Increase in this repressive mark serves to decrease gene expression. Our findings reveal a previously unreported role for SETDB2 in regulating fibroblast function in tissue repair. Moreover, our data suggest that the diabetic milieu promotes increased expression of SETDB2 which, in turn, may contribute to maintaining the impaired fibroblast function in diabetic wounds that hinders tissue repair.