The histone acetyltransferase MOF promotes macrophage inflammation in diabetic wounds.

Abstract

Abstract Macrophage (Mϕ) plasticity is essential for the repair and remodeling of wounds. However, under pathologic conditions such as type 2 diabetes (T2D), Mϕs exist in a chronic inflammatory state that drives continued tissue destruction and results in impaired wound healing. We have previously shown that Mϕs isolated from wounds in a murine model that mimics physiologic development of T2D (diet-induced obese mice; DIO) display increased levels of inflammatory cytokines at both a gene expression and protein level. Although the underlying mechanisms remain unclear, we and others have shown that Mϕ phenotype can be controlled by epigenetic modifications that alter gene expression. Our recent work provides evidence that the diabetic milieu alters gene expression and sets an “epigenetic signature” in myeloid cells that result in an exaggerated inflammatory phenotype and delayed wound healing in a murine model. Further, our recent work has found that the histone acetyl transferase, Males absent on the first (MOF), responsible for acetylation of lysine 16 on histone H4 (H4K16), was critical for expression of genes involved in fatty acid metabolism. In the present study, we find that wound Mϕs from DIO mice have increased expression of MOF at day 5, when Mϕs shift from a pro-inflammatory to an anti-inflammatory state within wound tissue. This change in MOF was accompanied by increased expression of components of MOF regulatory complexes, MSL1/2 and KANSL1. Our findings reveal a previously unreported role for MOF in promoting a pro-inflammatory state in innate immune cells. Moreover, our data suggest that the diabetic milieu promotes increased expression of MOF which, in turn, may contribute to maintaining the persistent inflammatory state in wound Mϕs.