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Cell Rep. 2018 Nov 20;25(8):2044-2052.e5. doi: 10.1016/j.celrep.2018.10.092.

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia.

Author information

1
Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
2
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HZ Amsterdam, the Netherlands.
3
Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
4
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
5
Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Biomedical Engineering and Physics, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
6
Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
7
Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Pettenkoferstrasse 9, 80336 Munich, Germany.
9
Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HZ Amsterdam, the Netherlands. Electronic address: j.vandenbossche@vumc.nl.

Abstract

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.

KEYWORDS:

Nrf2; atherosclerosis; cardiovascular disease; foam cells; hypercholesterolemia; immunometabolism; inflammation; macrophages; meta-inflammation; metabolic disease; pentose phosphate pathway

PMID:
30463003
DOI:
10.1016/j.celrep.2018.10.092
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