Abstract 14248: Obesity-Induced Abnormal Epigenetic Response in Macrophages Deteriorates Wound Healing

Abstract

Background: Macrophages play key roles in the normal wound healing process, and their dysregulation is linked with impaired wound healing in disease conditions such as diabetes and obesity. Epigenetic mechanism such as histone modification involves in macrophage dysregulation. Epigenetic response to hypoxic environment has implications in macrophage functions in inflammation. Whether obesity influences histone modification under hypoxia is unknown. Methods and Results: Wild-type mice were fed normal diet (ND) or high-fat diet (HFD) for 4-5 months to induce obesity. Bone marrow-derived macrophages (BMDMs) were obtained from both groups. BMDMs were treated in hypoxic condition (1% O 2 ) for 1 hour, and the enrichment of histone 3 lysine 4 tri-methylation (H3K4me3) in BMDMs was assessed with western blotting and high-content imaging analysis. We found that hypoxia increases total H3K4me3 levels in BMDMs from ND, whereas this hypoxia-induced H3K4me3 upregulation was abolished in BMDMs from HFD. ChIP-seq was performed to investigate detailed H3K4me3 landscape and revealed hypoxia-induced H3K4me4 enrichment in promoter regions targeted by a H3K4 demethylase Kdm5a, including Hoxb9 and Sart3 in BMDMs from ND but not from HFD. This is aligned with the role of Kdm5a as a rapid hypoxia sensor and indicates impaired pro-healing activity of macrophages in HFD. Mechanistically, paralleled western blot of phospho-Akt showed a linear correlation with H3K4me3 levels, supporting the previous finding that p-Akt negatively regulates nuclear translocation of Kdm5a. Conclusion: Obesity impairs the wound healing response of macrophages by modifying epigenetics via p-Akt/Kdm5a axis.