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

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

Author information

1
From the Section of Vascular Surgery, Department of Surgery (F.M.D., A.D., A.D.J., A.S.K., A.T.O., W.J.M., K.A.G.), University of Michigan, Ann Arbor.
2
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville (M.A.S.).
3
Department of Pathology (H.E., M.S., B.C., S.L.K.), University of Michigan, Ann Arbor.
4
Department of Internal Medicine (C.W., B.B.M.), University of Michigan, Ann Arbor.
5
Urological Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA (K.C.).
6
Department of Anesthesiology (S.M., M.E.), University of Michigan, Ann Arbor.
7
Biorepository Office of Research (V.B.), University of Michigan, Ann Arbor.
8
Department Microbiology and Immunology (B.B.M., K.A.G.), University of Michigan, Ann Arbor.

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

PMID:
31644352
PMCID:
PMC6818743
[Available on 2020-11-01]
DOI:
10.1161/ATVBAHA.119.312754

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