Macrophage-mediated lysine methyltransferase, Setdb2, regulates inflammation in wound healing

Abstract

Abstract Epigenetic regulation of macrophages can alter their function and impact tissue inflammation and wound repair. Unregulated inflammation at the wound level in inflammatory diseases like type 2 diabetes (T2D) leads to significant morbidity and mortality. Recent work by our group and others has shown that chromatin-modifying enzymes influence inflammatory gene expression in macrophages and other immune cells. Here we show that Setdb2, a histone methyltransferase, is induced in macrophages during the inflammatory phase of wound healing. Specifically, Setdb2 repressed expression of NF-κB-induced inflammatory genes, including IL-1B. This coincided with occupancy by Setdb2 at the IL-1B promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone 3 lysine 9 (H3K9me3) in bone marrow derived macrophages (BMDM). Mice with the inability to upregulate setdb2 in their macrophages (Setdb2f/fLyz2cre+) demonstrated impaired healing during the inflammatory phase of wound healing. This corresponded with decreased H3K9me3 at the promoter of IL-1B and other inflammatory genes in macrophages isolated from the wounds of these animals. Further, LPS was able to upregulate setdb2 expression in BMDM and hence TLR4 signaling may play a role in regulation of inflammation in wound tissue. This suggests that a Setdb2-mediated alteration of NF-κB pathways represents an important mechanism for successful wound healing.