Para-hydroxyphenylpyruvate inhibits the pro-inflammatory stimulation of macrophage preventing LPS-mediated nitro-oxidative unbalance and immunometabolic shift

Rosella Scrima, Marta Menga, Consiglia Pacelli, Francesca Agriesti, Olga Cela, Claudia Piccoli, Antonella Cotoia, Alessandra De Gregorio, Julia V. Gefter, Gilda Cinnella, Nazzareno Capitanio

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Targeting metabolism is emerging as a promising therapeutic strategy for modulation of the immune response in human diseases. In the presented study we used the lipopolysaccharide (LPS)-mediated activation of RAW 264.7 macrophage-like cell line as a model to investigate changes in the metabolic phenotype and to test the effect of p-hydroxyphenylpyruvate (pHPP) on it. pHPP is an intermediate of the PHE/TYR catabolic pathway, selected as analogue of the ethyl pyruvate (EP), which proved to exhibit antioxidant and anti-inflammatory activities. The results obtained show that LPS-priming of RAW 264.7 cell line to the activated M1 state resulted in up-regulation of the inducible nitric oxide synthase (iNOS) expression and consequently of NO production and in release of the pro-inflammatory cytokine IL-6. All these effects were prevented dose dependently by mM concentrations of pHPP more efficiently than EP. Respirometric and metabolic flux analysis of LPS-treated RAW 264.7 cells unveiled a marked metabolic shift consisting in downregulation of the mitochondrial oxidative phosphorylation and upregulation of aerobic glycolysis respectively. The observed respiratory failure in LPS-treated cells was accompanied with inhibition of the respiratory chain complexes I and IV and enhanced production of reactive oxygen species. Inhibition of the respiratory activity was also observed following incubation of human neonatal fibroblasts (NHDF-neo) with sera from septic patients. pHPP prevented all the observed metabolic alteration caused by LPS on RAW 264.7 or by septic sera on NHDF-neo. Moreover, we provide evidence that pHPP is an efficient reductant of cytochrome c. On the basis of the presented results a working model, linking pathogen-associated molecular patterns (PAMPs)-mediated immune response to mitochondrial oxidative metabolism, is put forward along with suggestions for its therapeutic control.

Original languageEnglish
Article numbere0188683
JournalPLoS One
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

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Macrophages
lipopolysaccharides
Lipopolysaccharides
macrophages
Cells
Metabolism
Up-Regulation
Metabolic Flux Analysis
cell lines
immune response
NADH dehydrogenase (ubiquinone)
Electron Transport Complex I
therapeutics
reducing agents
oxidative phosphorylation
aerobiosis
cytochrome c
Oxidative Phosphorylation
Reducing Agents
electron transport chain

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Para-hydroxyphenylpyruvate inhibits the pro-inflammatory stimulation of macrophage preventing LPS-mediated nitro-oxidative unbalance and immunometabolic shift. / Scrima, Rosella; Menga, Marta; Pacelli, Consiglia; Agriesti, Francesca; Cela, Olga; Piccoli, Claudia; Cotoia, Antonella; De Gregorio, Alessandra; Gefter, Julia V.; Cinnella, Gilda; Capitanio, Nazzareno.

In: PLoS One, Vol. 12, No. 11, e0188683, 01.11.2017.

Research output: Contribution to journalArticle

Scrima, R, Menga, M, Pacelli, C, Agriesti, F, Cela, O, Piccoli, C, Cotoia, A, De Gregorio, A, Gefter, JV, Cinnella, G & Capitanio, N 2017, 'Para-hydroxyphenylpyruvate inhibits the pro-inflammatory stimulation of macrophage preventing LPS-mediated nitro-oxidative unbalance and immunometabolic shift', PLoS One, vol. 12, no. 11, e0188683. https://doi.org/10.1371/journal.pone.0188683
Scrima, Rosella ; Menga, Marta ; Pacelli, Consiglia ; Agriesti, Francesca ; Cela, Olga ; Piccoli, Claudia ; Cotoia, Antonella ; De Gregorio, Alessandra ; Gefter, Julia V. ; Cinnella, Gilda ; Capitanio, Nazzareno. / Para-hydroxyphenylpyruvate inhibits the pro-inflammatory stimulation of macrophage preventing LPS-mediated nitro-oxidative unbalance and immunometabolic shift. In: PLoS One. 2017 ; Vol. 12, No. 11.
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AU - Cela, Olga

AU - Piccoli, Claudia

AU - Cotoia, Antonella

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AU - Gefter, Julia V.

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AU - Capitanio, Nazzareno

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AB - Targeting metabolism is emerging as a promising therapeutic strategy for modulation of the immune response in human diseases. In the presented study we used the lipopolysaccharide (LPS)-mediated activation of RAW 264.7 macrophage-like cell line as a model to investigate changes in the metabolic phenotype and to test the effect of p-hydroxyphenylpyruvate (pHPP) on it. pHPP is an intermediate of the PHE/TYR catabolic pathway, selected as analogue of the ethyl pyruvate (EP), which proved to exhibit antioxidant and anti-inflammatory activities. The results obtained show that LPS-priming of RAW 264.7 cell line to the activated M1 state resulted in up-regulation of the inducible nitric oxide synthase (iNOS) expression and consequently of NO production and in release of the pro-inflammatory cytokine IL-6. All these effects were prevented dose dependently by mM concentrations of pHPP more efficiently than EP. Respirometric and metabolic flux analysis of LPS-treated RAW 264.7 cells unveiled a marked metabolic shift consisting in downregulation of the mitochondrial oxidative phosphorylation and upregulation of aerobic glycolysis respectively. The observed respiratory failure in LPS-treated cells was accompanied with inhibition of the respiratory chain complexes I and IV and enhanced production of reactive oxygen species. Inhibition of the respiratory activity was also observed following incubation of human neonatal fibroblasts (NHDF-neo) with sera from septic patients. pHPP prevented all the observed metabolic alteration caused by LPS on RAW 264.7 or by septic sera on NHDF-neo. Moreover, we provide evidence that pHPP is an efficient reductant of cytochrome c. On the basis of the presented results a working model, linking pathogen-associated molecular patterns (PAMPs)-mediated immune response to mitochondrial oxidative metabolism, is put forward along with suggestions for its therapeutic control.

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