Acute and chronic inflammation alter immunometabolism in a cutaneous delayed-type hypersensitivity reaction (DTHR) mouse model

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Abstract

T-cell-driven immune responses are responsible for several autoimmune disorders, such as psoriasis vulgaris and rheumatoid arthritis. Identification of metabolic signatures in inflamed tissues is needed to facilitate novel and individualised therapeutic developments. Here we show the temporal metabolic dynamics of T-cell-driven inflammation characterised by nuclear magnetic resonance spectroscopy-based metabolomics, histopathology and immunohistochemistry in acute and chronic cutaneous delayed-type hypersensitivity reaction (DTHR). During acute DTHR, an increase in glutathione and glutathione disulfide is consistent with the ear swelling response and degree of neutrophilic infiltration, while taurine and ascorbate dominate the chronic phase, suggesting a switch in redox metabolism. Lowered amino acids, an increase in cell membrane repair-related metabolites and infiltration of T cells and macrophages further characterise chronic DTHR. Acute and chronic cutaneous DTHR can be distinguished by characteristic metabolic patterns associated with individual inflammatory pathways providing knowledge that will aid target discovery of specialised therapeutics.

Abstract

Nuclear magnetic resonance spectroscopy-based tissue metabolomics is used to define detailed temporal signatures of acute and chronic inflammation in cutaneous delayed-type hypersensitivity reaction.

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Most cited references 39

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Reactive oxygen species in inflammation and tissue injury.

Manish Mittal, Mohammad Rizwan Siddiqui, Khiem Vinh Tran … (2014)

Abstract Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.

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Succinate is an inflammatory signal that induces IL-1β through HIF-1α.

G M Tannahill, A. M. Curtis, J Adamik … (2013)

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

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Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis

Jasmine Chong, David Wishart, Jianguo Xia (2019)

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Author and article information

Contributors

Manfred Kneilling:

ORCID: http://orcid.org/0000-0001-9119-1970

Manfred.Kneilling@med.uni-tuebingen.de

Christoph Trautwein:

ORCID: http://orcid.org/0000-0003-4672-6395

Christoph.Trautwein@med.uni-tuebingen.de

Journal

Journal ID (nlm-ta): Commun Biol

Journal ID (iso-abbrev): Commun Biol

Title: Communications Biology

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2399-3642

Publication date (Electronic): 15 November 2022

Publication date PMC-release: 15 November 2022

Publication date Collection: 2022

Volume: 5

Electronic Location Identifier: 1250

Affiliations

[1 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, , Eberhard Karls University of Tübingen, ; Röntgenweg 13, 72076 Tübingen, Germany

[2 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, , Eberhard Karls University of Tübingen, ; Röntgenweg 11, 72076 Tübingen, Germany

[3 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Institute of Pathology and Neuropathology, Comprehensive Cancer Center, , Eberhard Karls University of Tübingen, ; Liebermasterstraße 8, 72076 Tübingen, Germany

[4 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Center for Preclinical Research, , Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ; Via Pace 9, 20100 Milan, Italy

[5 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Department of Dermatology, , Eberhard Karls University of Tübingen, ; Liebermeisterstraße 25, 72076 Tübingen, Germany

Author information

Laimdota Zizmare http://orcid.org/0000-0001-7208-3659

Bernd J. Pichler http://orcid.org/0000-0001-6784-5524

Manfred Kneilling http://orcid.org/0000-0001-9119-1970

Christoph Trautwein http://orcid.org/0000-0003-4672-6395

Article

Publisher ID: 4179

DOI: 10.1038/s42003-022-04179-x

PMC ID: 9666528

PubMed ID: 36380134

SO-VID: ce06cd6d-dd93-42ba-a922-2950f9da702e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 31 May 2022

Date accepted : 27 October 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);

Award ID: Germany’s Excellence Strategy - EXC 2180 – 390900677

Award ID: SFB TRR156, TP C03

Award ID: Germany’s Excellence Strategy - EXC 2180 – 390900677

Award Recipient : Leticia Quintanilla-Martinez Bernd J. Pichler Manfred Kneilling

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Keywords: metabolomics,chronic inflammation,autoimmune diseases,metabolic pathways

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Keywords: metabolomics, chronic inflammation, autoimmune diseases, metabolic pathways

Acute and chronic inflammation alter immunometabolism in a cutaneous delayed-type hypersensitivity reaction (DTHR) mouse model

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Most cited references 39

Reactive oxygen species in inflammation and tissue injury.

Succinate is an inflammatory signal that induces IL-1β through HIF-1α.

Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis

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