The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair
Copyright © 2019 Elsevier Inc. All rights reserved..
Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
| Errataetall: |
CommentIn: Immunity. 2019 Aug 20;51(2):199-201. - PMID 31433963 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
Immunity - 51(2019), 2 vom: 20. Aug., Seite 258-271.e5 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kimball, Andrew S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.12.2019 Date Revised 08.02.2021 published: Print-Electronic CommentIn: Immunity. 2019 Aug 20;51(2):199-201. - PMID 31433963 Citation Status MEDLINE |
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| doi: |
10.1016/j.immuni.2019.06.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM299619001 |
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| 100 | 1 | |a Kimball, Andrew S |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair |
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| 500 | |a Date Completed 12.12.2019 | ||
| 500 | |a Date Revised 08.02.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Immunity. 2019 Aug 20;51(2):199-201. - PMID 31433963 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a diabetes | |
| 650 | 4 | |a epigenetics | |
| 650 | 4 | |a gene expression and regulation | |
| 650 | 4 | |a histone | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a macrophages | |
| 650 | 4 | |a methylation | |
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| 650 | 7 | |a Uric Acid |2 NLM | |
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| 700 | 1 | |a denDekker, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Joshi, Amrita D |e verfasserin |4 aut | |
| 700 | 1 | |a Schaller, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a Bermick, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Xing, Xianying |e verfasserin |4 aut | |
| 700 | 1 | |a Burant, Charles F |e verfasserin |4 aut | |
| 700 | 1 | |a Obi, Andrea T |e verfasserin |4 aut | |
| 700 | 1 | |a Nysz, Dylan |e verfasserin |4 aut | |
| 700 | 1 | |a Robinson, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Ron |e verfasserin |4 aut | |
| 700 | 1 | |a Lukacs, Nicholas W |e verfasserin |4 aut | |
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| 700 | 1 | |a Gudjonsson, Johann E |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Bethany B |e verfasserin |4 aut | |
| 700 | 1 | |a Kunkel, Steve L |e verfasserin |4 aut | |
| 700 | 1 | |a Gallagher, Katherine A |e verfasserin |4 aut | |
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