JARID1C Regulates Macrophage Function in Diabetic Wounds 2299614

Abstract

Abstract Introduction Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and are increasing at a concerning rate. The injury response is a complex process that must proceed in an orderly and organized manner to restore homeostatic tissue function. Macrophages are highly plastic in tissue and are recruited in wounds following injury. In vivo, macrophages exist along a continuum where they initially exist in a pro-inflammatory state and then transition to an anti-inflammatory state to promote proliferation and remodeling phases. In T2D, this does not occur, and macrophages remain in an inflammatory state and serve to promote chronic inflammation. Methods Experiments were conducted using C57Bl/6 mice (WT) or Macrophage-selective deletion of Jarid1c transgenic mice (Jarid1c f/f Lyz2 Cre). These mice were placed on a normal diet (ND) and on a high fat diet to generate a Diet Induced Obesity (DIO) diabetic model. Mice were on the requisite diet for 12-16 weeks. Wound macrophages were isolated from the wound via EasySep Cdllb+ Isolation. Macrophage phenotype was assessed by qPCR and chromatin immunoprecipitation (ChIP) following DNase/Liberase digestion of wound tissue. Results Here, we identify JARID1C, a histone demethylase that removes the activating trimethyl mark on histone 3 lysine 4, as a critical regulator of inflammatory gene expression in macrophages. In DIO mice, wound macrophages exhibit reduced JARID1C expression. We demonstrate that JARID1C is required for the resolution of inflammation, enabling IL-6—dependent removal of H3K4me3 at promoters of inflammatory genes. Macrophage-specific deletion of JARID1C significantly delayed wound closure in the DIO wound model, establishing its functional importance in tissue repair. Conclusion Collectively, these findings suggest JARID1C acts as critical epigenetic regulator of macrophage function during wound healing and this axis may be a potential therapeutic target for improving wound healing in patients with T2D. Funding Source CTSA T32 TR004371 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)