PMID- 36574745
OWN - NLM
STAT- MEDLINE
DCOM- 20230117
LR  - 20230701
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 59
DP  - 2023 Feb
TI  - Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages.
PG  - 102591
LID - S2213-2317(22)00363-9 [pii]
LID - 10.1016/j.redox.2022.102591 [doi]
LID - 102591
AB  - Pathological conditions associated with dysfunctional wound healing are 
      characterized by impaired remodelling of extracellular matrix (ECM), increased 
      macrophage infiltration, and chronic inflammation. Macrophages also play an 
      important role in wound healing as they drive wound closure by secretion of 
      molecules like transforming growth factor beta-1 (TGF-beta). As the functions of 
      macrophages are regulated by their metabolism, local administration of small 
      molecules that alter this might be a novel approach for treatment of 
      wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived 
      metabolite that has been associated with resolution of macrophage-mediated 
      inflammation. However, its effects on macrophage wound healing functions are 
      unknown. In this study, we investigated the effects of the membrane-permeable 
      4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood 
      monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 
      mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus 
      lipopolysaccharide (LPS). Likely as a consequence of this, the production of the 
      inflammatory mediators like tumor necrosis factor (TNF)-alpha and cyclooxygenase 
      (COX)-2 were also reduced. On the transcriptional level, 4-OI increased 
      expression of the gene coding for TGF-beta (TGFB1), whereas expression of the 
      collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface 
      levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were 
      increased in these cells. To directly investigate the effect of 4-OI on 
      scavenging of ECM by macrophages, we developed an assay to measure uptake of 
      fibrous collagen. We observed that LPS promoted collagen uptake and that this was 
      reversed by 4-OI-induced signaling of nuclear factor erythroid 2-related factor 2 
      (NRF2), a regulator of cellular resistance to oxidative stress and the reduced 
      glycolytic capacity of the macrophage. These results indicate that 4-OI lowers 
      macrophage inflammation, likely promoting a more wound-resolving phenotype.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Maassen, Sjors
AU  - Maassen S
AD  - Department of Molecular Immunology, Groningen Biomolecular Sciences and 
      Biotechnology, University of Groningen, Groningen, the Netherlands.
FAU - Coenen, Britt
AU  - Coenen B
AD  - Department of Molecular Immunology, Groningen Biomolecular Sciences and 
      Biotechnology, University of Groningen, Groningen, the Netherlands.
FAU - Ioannidis, Melina
AU  - Ioannidis M
AD  - Department of Molecular Immunology, Groningen Biomolecular Sciences and 
      Biotechnology, University of Groningen, Groningen, the Netherlands.
FAU - Harber, Karl
AU  - Harber K
AD  - Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular 
      Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam 
      Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, 
      Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
FAU - Grijpstra, Pieter
AU  - Grijpstra P
AD  - Department of Molecular Immunology, Groningen Biomolecular Sciences and 
      Biotechnology, University of Groningen, Groningen, the Netherlands.
FAU - Van den Bossche, Jan
AU  - Van den Bossche J
AD  - Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular 
      Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam 
      Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam UMC, 
      Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
FAU - van den Bogaart, Geert
AU  - van den Bogaart G
AD  - Department of Molecular Immunology, Groningen Biomolecular Sciences and 
      Biotechnology, University of Groningen, Groningen, the Netherlands; Department of 
      Medical Biology and Pathology, University Medical Center Groningen, Groningen, 
      the Netherlands. Electronic address: G.van.den.bogaart@rug.nl.
LA  - eng
GR  - 862137/ERC_/European Research Council/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221224
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - Q4516562YH (itaconic acid)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - 9007-34-5 (Collagen)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Humans
MH  - *Lipopolysaccharides/adverse effects
MH  - *Macrophages/metabolism
MH  - Inflammation/metabolism
MH  - Phenotype
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Cyclooxygenase 2/metabolism
MH  - Collagen/metabolism
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC9800195
COIS- Declaration of competing interest All authors declare that they have no conflicts 
      of interest.
EDAT- 2022/12/28 06:00
MHDA- 2023/01/18 06:00
PMCR- 2022/12/24
CRDT- 2022/12/27 18:03
PHST- 2022/11/08 00:00 [received]
PHST- 2022/12/21 00:00 [revised]
PHST- 2022/12/23 00:00 [accepted]
PHST- 2022/12/28 06:00 [pubmed]
PHST- 2023/01/18 06:00 [medline]
PHST- 2022/12/27 18:03 [entrez]
PHST- 2022/12/24 00:00 [pmc-release]
AID - S2213-2317(22)00363-9 [pii]
AID - 102591 [pii]
AID - 10.1016/j.redox.2022.102591 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Feb;59:102591. doi: 10.1016/j.redox.2022.102591. Epub 2022 Dec 
      24.