Journal article
The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair
Immunity (Cambridge, Mass.), Vol.51(2), pp.258-271.e5
08/20/2019
DOI: 10.1016/j.immuni.2019.06.015
PMCID: PMC6703945
PMID: 31350176
Abstract
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-kappa B binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) beta, and under diabetic conditions, this IFN beta-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.
Details
- Title: Subtitle
- The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair
- Creators
- Andrew S. Kimball - University of Michigan–Ann ArborFrank M. Davis - University of Michigan–Ann ArborAaron DenDekker - University of Michigan–Ann ArborAmrita D. Joshi - University of Michigan–Ann ArborMatthew A. Schaller - University of FloridaJennifer Bermick - University of Michigan–Ann ArborXianying Xing - University of Michigan–Ann ArborCharles F. Burant - University of Michigan–Ann ArborAndrea T. Obi - University of Michigan–Ann ArborDylan Nysz - University of Michigan–Ann ArborScott Robinson - University of Michigan–Ann ArborRon Allen - Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USANicholas W. Lukacs - University of Michigan–Ann ArborPeter K. Henke - University of Michigan–Ann ArborJohann E. Gudjonsson - University of Michigan–Ann ArborBethany B. Moore - University of Michigan–Ann ArborSteve L. Kunkel - University of Michigan–Ann ArborKatherine A. Gallagher - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Immunity (Cambridge, Mass.), Vol.51(2), pp.258-271.e5
- Publisher
- Elsevier
- DOI
- 10.1016/j.immuni.2019.06.015
- PMID
- 31350176
- PMCID
- PMC6703945
- ISSN
- 1074-7613
- eISSN
- 1097-4180
- Number of pages
- 19
- Grant note
- RO1-HL137919; NIH-T32 HL076123; NIH-F32 DK-117545-01 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32HL076123 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) P30AR075043 / NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) Doris Duke Foundation; Doris Duke Charitable Foundation (DDCF) F32DK117545 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01AI036302 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 08/20/2019
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984354043502771
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