The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.
Aged
Animals
Carrier Proteins
/ genetics
Cell Differentiation
Cells, Cultured
Diabetes Mellitus, Type 2
/ metabolism
Disease Models, Animal
Female
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Macrophages
/ physiology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Nuclear Proteins
/ genetics
Phenotype
Uric Acid
/ metabolism
Wound Healing
diabetes
epigenetics
gene expression and regulation
histone
inflammation
macrophages
methylation
monocytes
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
20 08 2019
20 08 2019
Historique:
received:
12
11
2018
revised:
18
04
2019
accepted:
19
06
2019
pubmed:
28
7
2019
medline:
18
12
2019
entrez:
28
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31350176
pii: S1074-7613(19)30285-7
doi: 10.1016/j.immuni.2019.06.015
pmc: PMC6703945
mid: NIHMS1533059
pii:
doi:
Substances chimiques
Carrier Proteins
0
Nuclear Proteins
0
SETBP1 protein, human
0
Uric Acid
268B43MJ25
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Setdb2 protein, mouse
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
258-271.e5Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK119083
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI036302
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137919
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR075043
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL076123
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL144481
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK089503
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK117545
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI117229
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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