Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing
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.
| Errataetall: |
CommentIn: Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2205-2206. - PMID 31644353 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
Arteriosclerosis, thrombosis, and vascular biology - 39(2019), 11 vom: 22. Nov., Seite 2353-2366 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Davis, Frank M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.04.2020 Date Revised 14.02.2024 published: Print-Electronic CommentIn: Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2205-2206. - PMID 31644353 Citation Status MEDLINE |
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| doi: |
10.1161/ATVBAHA.119.312754 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM302493433 |
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| 100 | 1 | |a Davis, Frank M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 08.04.2020 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2205-2206. - PMID 31644353 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Schaller, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a Dendekker, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Joshi, Amrita D |e verfasserin |4 aut | |
| 700 | 1 | |a Kimball, Andrew S |e verfasserin |4 aut | |
| 700 | 1 | |a Evanoff, Holly |e verfasserin |4 aut | |
| 700 | 1 | |a Wilke, Carol |e verfasserin |4 aut | |
| 700 | 1 | |a Obi, Andrea T |e verfasserin |4 aut | |
| 700 | 1 | |a Melvin, William J |e verfasserin |4 aut | |
| 700 | 1 | |a Cavassani, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Scola, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Carson, Beau |e verfasserin |4 aut | |
| 700 | 1 | |a Moser, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Blanc, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Engoren, Milo |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Bethany B |e verfasserin |4 aut | |
| 700 | 1 | |a Kunkel, Steven L |e verfasserin |4 aut | |
| 700 | 1 | |a Gallagher, Katherine A |e verfasserin |4 aut | |
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