title: Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal.
abstract: The mechanism by which oxidative stress induces inflammation and vice versa is unclear but is of great importance, being apparently linked to many chronic inflammatory diseases. We show here that inflammatory stimuli induce release of oxidized peroxiredoxin-2 (PRDX2), a ubiquitous redox-active intracellular enzyme. Once released, the extracellular PRDX2 acts as a redox-dependent inflammatory mediator, triggering macrophages to produce and release TNF-α. The oxidative coupling of glutathione (GSH) to PRDX2 cysteine residues (i.e., protein glutathionylation) occurs before or during PRDX2 release, a process central to the regulation of immunity. We identified PRDX2 among the glutathionylated proteins released in vitro by LPS-stimulated macrophages using mass spectrometry proteomic methods. Consistent with being part of an inflammatory cascade, we find that PRDX2 then induces TNF-α release. Unlike classical inflammatory cytokines, PRDX2 release does not reflect LPS-mediated induction of mRNA or protein synthesis; instead, PRDX2 is constitutively present in macrophages, mainly in the reduced form, and is released in the oxidized form on LPS stimulation. Release of PRDX2 is also observed in human embryonic kidney cells treated with TNF-α. Importantly, the PRDX2 substrate thioredoxin (TRX) is also released along with PRDX2, enabling an oxidative cascade that can alter the -SH status of surface proteins and thereby facilitate activation via cytokine and Toll-like receptors. Thus, our findings suggest a model in which the release of PRDX2 and TRX from macrophages can modify the redox status of cell surface receptors and enable induction of inflammatory responses. This pathway warrants further exploration as a potential novel therapeutic target for chronic inflammatory diseases.
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;
authors.forename: Sonia
authors.initials: S
authors.lastname: Salzano
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;Department of Public Health and Infectious Diseases, Institut Pasteur, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Checconi
authors.affiliation: Institute for Medical Biochemistry and Molecular Biology, University Medicine, Ernst-Moritz-Arndt University, 17475 Greifswald, Germany;
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Hanschmann
authors.affiliation: Institute for Medical Biochemistry and Molecular Biology, University Medicine, Ernst-Moritz-Arndt University, 17475 Greifswald, Germany;
authors.forename: Christopher Horst
authors.initials: CH
authors.lastname: Lillig
authors.affiliation: School of Life Sciences, University of Sussex, Falmer BN19RY, United Kingdom;
authors.forename: Lucas D
authors.initials: LD
authors.lastname: Bowler
authors.affiliation: Institute for Research and Innovation in Biomedicine, Rouen University, 76821 Rouen, France;Platform in Proteomics PISSARO, 76821 Mont-Saint-Aignan, France; and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chan
authors.affiliation: Institute for Research and Innovation in Biomedicine, Rouen University, 76821 Rouen, France;Platform in Proteomics PISSARO, 76821 Mont-Saint-Aignan, France; and.
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;
authors.forename: Manuela
authors.initials: M
authors.lastname: Mengozzi
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;
authors.forename: Lucia
authors.initials: L
authors.lastname: Coppo
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;
authors.forename: Sandra
authors.initials: S
authors.lastname: Sacre
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Kondala R
authors.initials: KR
authors.lastname: Atkuri
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Bita
authors.initials: B
authors.lastname: Sahaf
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Herzenberg
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom;
authors.forename: Lisa
authors.initials: L
authors.lastname: Mullen
authors.affiliation: Brighton and Sussex Medical School, Falmer BN19RY, United Kingdom; p.ghezzi@bsms.ac.uk.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D054464:Peroxiredoxins; D005978:Glutathione
keywords: cysteine oxidation; redox proteomics; thiol oxidation
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