Classically activated (M1) macrophages are known to play a role in the development of chronic
inflammation associated with impaired wound healing in
type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D
wounds is unknown. Since epigenetic
enzymes can direct macrophage phenotypes, we assessed the role of
histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive
histone methylation mark, H3K27me3, is decreased at the promoter of the
IL-12 gene in BM progenitors and this epigenetic signature is passed down to
wound macrophages in a murine model of
glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact
wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives
IL-12 production in macrophages and that
IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained
inflammation associated with nonhealing
wounds. Hence,
histone demethylase inhibitor-based
therapy may represent a novel treatment option for diabetic
wounds.