Epigenetic Regulation Of The Tlr4 Pathway In Macrophages Via S-Adenosyl Methionine Results In Impaired Wound Healing In Diabetes

Macrophage (Mφ) plasticity, allowing the transition of Mφs from an inflammatory to a reparative phenotype, is critical for normal wound healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to impaired resolution of Mφ inflammation. Although the mechanisms responsible for the persistent inflammatory phenotype in T2D wounds are unknown, recent investigations have revealed that cellular metabolites can alter Mφ function providing a link between metabolism and innate immunity. Further, there is increasing evidence that epigenetic mechanisms control Mφ function. The purpose of this study was to investigate if altered Mφ metabolism in T2D induces epigenetic modifications resulting in derangements in Mφ inflammation and impaired wound healing. Using the murine diet induce obesity (DIO) wound model, we demonstrate that diabetic bone marrow derived macrophages (BMDM) and wound Mφs display a hyperinflammatory phenotype following injury with increased expression of toll-like receptor (TLR) 4 signaling and proinflammatory cytokines (IL-1β and TNFα). Given that histone methylation has previously been shown by our group to influence Mφ phenotype, we examined H3K4 trimethylation on the TLR4 promoter and found a significant increase in DIO BMDMs and wound Mφs. To evaluate the impact of Mφ metabolites on inflammation we performed a LC-MS metabolite expression analysis demonstrating significant upregulation of the methyl donor, S-adenosyl methionine (SAM), which participates in histone methylation, and its rate limiting enzyme, MAT2a, in diabetic BMDMs. In summary, these results suggest that increased levels of the metabolite SAM in diabetic Mφs contribute to an inflammatory Mφ phenotype via increased H3K4 methylation at the TLR4 promoter. Disclosure F.M. Davis: None. A.D. denDekker: None. A.S. Kimball: None. A. Boniakowski: None. A. Joshi: None. M. ElAzzouny: Employee; Self; Agilent Technologies. C. Burant: Stock/Shareholder; Self; Metabolic Solutions Development Company. K. Gallagher: None. Funding National Institutes of Health