A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Jeroen Baardman, Sanne G S Verberk, Koen H M Prange, Michel van Weeghel, Saskia van der Velden, Dylan G Ryan, Rob C I Wüst, Annette E Neele, Dave Speijer, Simone W Denis, Maarten E Witte, Riekelt H Houtkooper, Luke A O'neill, Elena V Knatko, Albena T Dinkova-Kostova, Esther Lutgens, Menno P J de Winther, Jan Van den Bossche (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)2044-2052.e5
Number of pages15
JournalCell Reports
Volume25
Issue number8
DOIs
Publication statusPublished - 20 Nov 2018

Fingerprint

Pentoses
Pentose Phosphate Pathway
Macrophages
Hypercholesterolemia
Metabolism
Phosphates
Oxidative stress
Dyslipidemias
Respiration
Oxidative Stress
Chemical activation
Cytokines
Phenotype

Keywords

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

Cite this

Baardman, J., Verberk, S. G. S., Prange, K. H. M., van Weeghel, M., van der Velden, S., Ryan, D. G., ... Van den Bossche, J. (2018). A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. Cell Reports, 25(8), 2044-2052.e5. https://doi.org/10.1016/j.celrep.2018.10.092
Baardman, Jeroen ; Verberk, Sanne G S ; Prange, Koen H M ; van Weeghel, Michel ; van der Velden, Saskia ; Ryan, Dylan G ; Wüst, Rob C I ; Neele, Annette E ; Speijer, Dave ; Denis, Simone W ; Witte, Maarten E ; Houtkooper, Riekelt H ; O'neill, Luke A ; Knatko, Elena V ; Dinkova-Kostova, Albena T ; Lutgens, Esther ; de Winther, Menno P J ; Van den Bossche, Jan. / A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. In: Cell Reports. 2018 ; Vol. 25, No. 8. pp. 2044-2052.e5.
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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.",
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Baardman, J, Verberk, SGS, Prange, KHM, van Weeghel, M, van der Velden, S, Ryan, DG, Wüst, RCI, Neele, AE, Speijer, D, Denis, SW, Witte, ME, Houtkooper, RH, O'neill, LA, Knatko, EV, Dinkova-Kostova, AT, Lutgens, E, de Winther, MPJ & Van den Bossche, J 2018, 'A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia', Cell Reports, vol. 25, no. 8, pp. 2044-2052.e5. https://doi.org/10.1016/j.celrep.2018.10.092

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. / Baardman, Jeroen; Verberk, Sanne G S; Prange, Koen H M; van Weeghel, Michel; van der Velden, Saskia; Ryan, Dylan G; Wüst, Rob C I; Neele, Annette E; Speijer, Dave; Denis, Simone W; Witte, Maarten E; Houtkooper, Riekelt H; O'neill, Luke A; Knatko, Elena V; Dinkova-Kostova, Albena T; Lutgens, Esther; de Winther, Menno P J; Van den Bossche, Jan (Lead / Corresponding author).

In: Cell Reports, Vol. 25, No. 8, 20.11.2018, p. 2044-2052.e5.

Research output: Contribution to journalArticle

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AU - Verberk, Sanne G S

AU - Prange, Koen H M

AU - van Weeghel, Michel

AU - van der Velden, Saskia

AU - Ryan, Dylan G

AU - Wüst, Rob C I

AU - Neele, Annette E

AU - Speijer, Dave

AU - Denis, Simone W

AU - Witte, Maarten E

AU - Houtkooper, Riekelt H

AU - O'neill, Luke A

AU - Knatko, Elena V

AU - Dinkova-Kostova, Albena T

AU - Lutgens, Esther

AU - de Winther, Menno P J

AU - Van den Bossche, Jan

N1 - Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. J.V.d.B. received a VENI grant from ZonMW (91615052) and a NetherlandsHeart Foundation junior postdoctoral grant (2013T003) and senior fellowship(2017T048). M.P.J.d.W. is an established investigator of the Netherlands HeartFoundation, is supported by grants from the Netherlands Heart Foundationand Spark-Holding BV (2015B002), the European Union (ITN grant EPIMACand REPROGRAM [EU Horizon 2020]), and Fondation Leducq (16CVD-01),and holds an AMC fellowship. We acknowledge support from the NetherlandsCardioVascular Research Initiative, Dutch Federation of University MedicalCenters, the Netherlands Organisation for Health Research and Development,the Royal Netherlands Academy of Sciences (CVON 2011-19 and CVON 2017-20) and Cancer Research UK (C20953/A18644). We thank Tadeja Rezen, PeterJuvan, and Damjana Rozman for the GEO: GSE13985 dataset details

PY - 2018/11/20

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AB - 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.

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KW - cardiovascular disease

KW - foam cells

KW - hypercholesterolemia

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KW - macrophages

KW - meta-inflammation

KW - metabolic disease

KW - pentose phosphate pathway

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Baardman J, Verberk SGS, Prange KHM, van Weeghel M, van der Velden S, Ryan DG et al. A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. Cell Reports. 2018 Nov 20;25(8):2044-2052.e5. https://doi.org/10.1016/j.celrep.2018.10.092