J Immunol. 2025 Aug 7:vkaf156. doi: 10.1093/jimmun/vkaf156. Online ahead of print.
ABSTRACT
Diet-induced obesity leads to dysregulated myelopoiesis and nonresolving inflammation. Such dysregulation could involve epigenetic reprogramming, which can induce long-term changes in hematopoietic stem and progenitor cells (HSPCs). However, whether and how obesity-dysregulated HSPCs impact myelopoiesis in response to tissue injury are not fully understood. Here, we tested the hypothesis that obesity induces oxidative stress and histone H3 lysine-4 trimethylation (H3K4me3) in HSPCs, programming enhanced myelopoiesis and persistent inflammation, leading to impaired tissue recovery. Transfer of bone marrow HSPCs from high-fat diet-induced obese mice (HFD-HSPCs) to lean recipients was sufficient to drive nonresolving myelopoiesis and impaired tissue recovery from hindlimb ischemia. HFD-HSPCs exhibited increased oxidative stress that drives elevated H3K4me3 and reduced KDM5 demethylase activity. CUT&Tag (cleavage under targets and tagmentation) analysis revealed H3K4me3 enrichment at cell cycling regulating E2F targets during myeloid differentiation and Tlr4 gene promoter in HFD-HSPCs. Such enrichment is associated with increased TLR4-driven myelopoiesis in vitro, increased inflammatory myelopoiesis during hindlimb ischemia, and myeloid bias after serial transplantations in lean recipients. Knockout of KDM5A, an H3K4me3 demethylase and negative regulator of E2F activity, increased H3K4me3 in HSPCs, enhanced TLR4-driven myelopoiesis in vitro, and increased myelopoiesis in vivo. Furthermore, cyclosporine A treatment in HSPCs ex vivo reduced oxidative stress, normalized H3K4me3 levels, and mitigated enhanced myelopoiesis in HSPCs in HFD mice. Our findings suggest that oxidative stress by diet-induced obesity enhances H3K4me3 levels and increases myelopoiesis in HSPCs, leading to persistent inflammation and impaired recovery from hindlimb ischemia.
PMID:40795290 | DOI:10.1093/jimmun/vkaf156