Metabolic Syndrome Induces Long Lasting Phenotype In Bone Marrow-Derived Macrophages And Their Progenitor Cells Through Oxidative Stress And Histone H3-Lysine 4 Methylation State

Metabolic syndrome is associated with low-grade inflammation and accumulation of inflammatory macrophages with largely unknown mechanisms. Here we report that bone marrow-derived macrophages (BMM) and their progenitor cells develop long lasting pro-inflammatory phenotype in metabolic syndrome. Using mice fed a high-fat diet (HFD) or a normal diet (ND), we found that BMM generated from HFD mice (BMM-HFD) exhibit higher transcription activities of pro-inflammatory genes than BMM generated from ND mice (BMM-ND). This is associated with increased oxidative stress (2.7-fold) and histone H3-lysine 4 tri-methylation (H3K4me3)( %), along with increased Set7 H3K4 methyltransferase (41%), in BMM-HFD. KDM5A H3K4 demethylase, however, is not changed in its levels but in its subcellular localization—increased extranuclear localization—in BMM-HFD. In addition, lower nuclear KDM5 enzymic activity was found in their BM progenitor cells (40%), and it was reversed by reduction of oxidative stress, resulting in reduction in H3K4me3 levels in those cells (33%). ChIP-PCR analysis revealed that H3K4me3 is increased at promoter lesions of potential KDM5A-targeted genes such as Tnf , Il6 and Cdkn2a . Moreover, adoptive transfer experiment in hindlimb ischemia, BM progenitor cells from HFD mice induce accumulation of pro-inflammatory macrophages, establishing a link between BM progenitor cells and macrophages in vivo. In summary, our result suggest that metabolic syndrome induces oxidative stress at the BM progenitor level, which causes long lasting inflammatory phenotype of their derived macrophages in vitro and in vivo. This causal effect may be mediated by oxidative stress and enzymes regulating H3K4me3.