The STAT3-SETDB2 Axis Dictates NFκB-mediated Inflammation in Macrophages during Wound Repair

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified the histone methyltransferase, SETDB2, in macrophages drives tissue repair by repressing NFκB-mediated inflammation. Complementary ATAC and RNA sequencing of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NFkB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages yet, paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NFKB component, RELA, leading to increased RELA/NFKB-mediated inflammatory gene expression. Further, RNA sequencing in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally co-regulate overlapping genes. Finally, in diabetic wound macrophages STAT3 expression and STAT3-SETDB2 binding were increased. As such, we identify what we believe to be a novel SETDB2-STAT3 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.