The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

Abstract

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)–mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1f/fLyz2Cre+ mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF

“…This switch is significantly impaired in obesity/T2D and results in chronic inflammation and nonhealing wounds; however, the etiology is unclear. We and others have previously identified that chronic inflammation in diabetic wounds is governed by epigenetic regulation of macrophages (12)(13)(14)(15)(16). In this study, we identify that the HAT MOF regulates inflammation in macrophages during normal and diabetic wound repair.…”

“…Sustained inflammation due to the inability of wound macrophages to transition to the regeneration stage necessary for normal skin repair is a hallmark of impaired wound healing associated with diseases such as type 2 diabetes (T2D) (6)(7)(8)(9)(10)(11). The mechanisms regulating this failed macrophage transition are not completely clear, but recent evidence suggests that epigenetic signatures can drive prolonged inflammation in diabetic wounds (12)(13)(14)(15)(16). Our group and others have identified that diabetic wound macrophages exhibit changes in histone methylation that promote a proinflammatory phenotype (12,14,16).…”

“…The mechanisms regulating this failed macrophage transition are not completely clear, but recent evidence suggests that epigenetic signatures can drive prolonged inflammation in diabetic wounds (12)(13)(14)(15)(16). Our group and others have identified that diabetic wound macrophages exhibit changes in histone methylation that promote a proinflammatory phenotype (12,14,16). Specifically, we have shown that MLL1 and JMJD3; a histone methyltransferase and histone demethylase, respectively, are altered in T2D macrophages, drive production of proinflammatory cytokines, and establish a proinflammatory feedback loop leading to uncontrolled inflammation (12,14,16).…”

Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing

“…We used a gating strategy selecting live, lineage − (CD3 − , CD19 − Ter119 − , NK1.1 − ), nonneutrophil (Ly6G − ), CD11b + cells, as previously described ( Fig. 2A) [29,30]. It has been previously documented by our group and others that Ly6C Hi demonstrate a proinflammatory phenotype, whereas Ly6C Lo cells demonstrate a reparative phenotype [8,13,[31][32][33].…”

Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses

“…JMJD3, a major regulator of macrophage activation, has been involved in type‐II diabetes, by driving pro‐inflammatory IL‐ 12 production in murine macrophages (Gallagher et al, ). Furthermore, monocytes from type‐II diabetic patients exhibit increased MLL1 methyltransferase compared to healthy controls (Kimball et al, ). In psoriasis patients, mRNA of Ezh2 and Suv39h1 methyltransferases were found increased, however, no significant differences in H3K27 and H3K4 global methylation pattern was observed (Zhang et al, ).…”