Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal

Sonia Salzano, Paola Checconi, Eva-Maria Hanschmann, Christopher Lillig, Lucas Bowler, P. Chan, David Vaudry, Manuela Mengozzi, Lucia Coppo, Sandra Sacre, Kondala R. Atkuri, Bita Sahaf, Leonard A. Herzenberg, Leonore A. Herzenberg, Lisa Mullen, Pietro Ghezzi

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)12157-12162
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume111
Issue number33
DOIs
Publication statusPublished - 19 Aug 2014

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Peroxiredoxins
Oxidative Stress
Inflammation
Macrophages
Oxidation-Reduction
Thioredoxins
Chronic Disease
Oxidative Coupling
Cytokines
Proteins
Toll-Like Receptors
Cell Surface Receptors
Proteomics
Glutathione
Cysteine
Immunity
Mass Spectrometry
Membrane Proteins

Keywords

  • cysteine oxidation
  • thiol oxidation
  • redox proteomics

Cite this

Salzano, Sonia ; Checconi, Paola ; Hanschmann, Eva-Maria ; Lillig, Christopher ; Bowler, Lucas ; Chan, P. ; Vaudry, David ; Mengozzi, Manuela ; Coppo, Lucia ; Sacre, Sandra ; Atkuri, Kondala R. ; Sahaf, Bita ; Herzenberg, Leonard A. ; Herzenberg, Leonore A. ; Mullen, Lisa ; Ghezzi, Pietro. / Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. In: Proceedings of the National Academy of Sciences. 2014 ; Vol. 111, No. 33. pp. 12157-12162.
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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.",
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Salzano, S, Checconi, P, Hanschmann, E-M, Lillig, C, Bowler, L, Chan, P, Vaudry, D, Mengozzi, M, Coppo, L, Sacre, S, Atkuri, KR, Sahaf, B, Herzenberg, LA, Herzenberg, LA, Mullen, L & Ghezzi, P 2014, 'Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal', Proceedings of the National Academy of Sciences, vol. 111, no. 33, pp. 12157-12162. https://doi.org/10.1073/pnas.1401712111

Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. / Salzano, Sonia; Checconi, Paola; Hanschmann, Eva-Maria; Lillig, Christopher; Bowler, Lucas; Chan, P.; Vaudry, David; Mengozzi, Manuela; Coppo, Lucia; Sacre, Sandra; Atkuri, Kondala R.; Sahaf, Bita; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Mullen, Lisa; Ghezzi, Pietro.

In: Proceedings of the National Academy of Sciences, Vol. 111, No. 33, 19.08.2014, p. 12157-12162.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal

AU - Salzano, Sonia

AU - Checconi, Paola

AU - Hanschmann, Eva-Maria

AU - Lillig, Christopher

AU - Bowler, Lucas

AU - Chan, P.

AU - Vaudry, David

AU - Mengozzi, Manuela

AU - Coppo, Lucia

AU - Sacre, Sandra

AU - Atkuri, Kondala R.

AU - Sahaf, Bita

AU - Herzenberg, Leonard A.

AU - Herzenberg, Leonore A.

AU - Mullen, Lisa

AU - Ghezzi, Pietro

PY - 2014/8/19

Y1 - 2014/8/19

N2 - 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.

AB - 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.

KW - cysteine oxidation

KW - thiol oxidation

KW - redox proteomics

U2 - 10.1073/pnas.1401712111

DO - 10.1073/pnas.1401712111

M3 - Article

VL - 111

SP - 12157

EP - 12162

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 33

ER -