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Scrima 2017 PLOS ONE

From Bioblast
Publications in the MiPMap
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 12:e0188683.

Β» PMID: 29176872 Open Access

Scrima R, Menga M, Pacelli C, Agriesti F, Cela O, Piccoli C, Cotoia A, De Gregorio A, Gefter JV, Cinnella G, Capitanio N (2017) PLOS ONE

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.

β€’ Bioblast editor: Kandolf G β€’ O2k-Network Lab: IT Foggia Capitanio N

Labels: MiParea: Respiration, Comparative MiP;environmental MiP 

Organism: Human, Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell, Blood cells, Fibroblast, Macrophage-derived  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

Labels, 2018-02