Details

Autor(en) / Beteiligte

• Davis, Frank M
• Schaller, Matthew A
• Dendekker, Aaron
• Joshi, Amrita D
• Kimball, Andrew S
• Evanoff, Holly
• Wilke, Carol
• Obi, Andrea T
• Melvin, William J
• Cavassani, Karen
• Scola, Melissa
• Carson, Beau
• Moser, Stephanie
• Blanc, Victoria
• Engoren, Milo
• Moore, Bethany B
• Kunkel, Steven L
• Gallagher, Katherine A

Titel

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

Ist Teil von

• Arteriosclerosis, thrombosis, and vascular biology, 2019-11, Vol.39 (11), p.2353-2366

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 , 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 compared with nonseptic controls. 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.