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Redox Biology
Article . 2022
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Redox Biology
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Redox Biology
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Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages

Authors: Maassen, Sjors; Coenen, Britt; Ioannidis, Melina; Harber, Karl; Grijpstra, Pieter; Van den Bossche, Jan; van den Bogaart, Geert;

Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages

Abstract

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-β). 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)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-β (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.

Country
Netherlands
Keywords

Lipopolysaccharides, Inflammation, Medicine (General), Tumor Necrosis Factor-alpha, QH301-705.5, Macrophages, Organic Chemistry, Clinical Biochemistry, Biochemistry, Phenotype, R5-920, Cyclooxygenase 2, Transforming Growth Factor beta, Humans, Collagen, Biology (General)

65 references, page 1 of 7

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[7] E.L. Mills, et al., Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1, Nature 556 (2018) 113-117. [OpenAIRE]

[8] W. Qin, et al., Chemoproteomic profiling of itaconation by bioorthogonal probes in inflammatory macrophages, Cite This: J. Am. Chem. Soc. 142 (2020) 10894-10898.

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
10
Top 10%
Average
Top 10%
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