Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing

Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2353-2366. doi: 10.1161/ATVBAHA.119.312754. Epub 2019 Sep 5.

Abstract

Objective: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of Mll1, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in MLL1 compared with nonseptic controls.

Conclusions: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.

Keywords: epigenetic; histones; inflammation; macrophages; sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / physiology
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Female
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / genetics
  • Humans
  • Immune Tolerance
  • Inflammation / physiopathology*
  • Macrophages / physiology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • NF-kappa B / genetics
  • Promoter Regions, Genetic
  • Sepsis / genetics*
  • Sepsis / metabolism
  • Sepsis / physiopathology*
  • Wound Healing / physiology*

Substances

  • Cytokines
  • Histones
  • NF-kappa B
  • histone H3 trimethyl Lys4
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse