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

doi:10.1016/j.celrep.2018.10.092

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^*

^*Corresponding author for this work

Physiology

Research output: Contribution to Journal › Article › Academic › peer-review

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. The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those “foam cell” macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage function.

Original language	English
Pages (from-to)	2044-2052.e5
Number of pages	23
Journal	Cell Reports
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2018.10.092
Publication status	Published - 20 Nov 2018

Funding

J.V.d.B. received a VENI grant from ZonMW ( 91615052 ) and a Netherlands Heart Foundation junior postdoctoral grant ( 2013T003 ) and senior fellowship ( 2017T048 ). M.P.J.d.W. is an established investigator of the Netherlands Heart Foundation, is supported by grants from the Netherlands Heart Foundation and Spark-Holding BV ( 2015B002 ), the European Union ( ITN grant EPIMAC and REPROGRAM [EU Horizon 2020]), and Fondation Leducq ( 16CVD-01 ), and holds an AMC fellowship. We acknowledge support from the Netherlands CardioVascular Research Initiative , Dutch Federation of University Medical Centers , 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, Peter Juvan, and Damjana Rozman for the GEO: GSE13985 dataset details.

Funders	Funder number
Dutch Federation of University Medical Centers
Netherlands CardioVascular Research Initiative
Netherlands Heart Foundation	2017T048, 2013T003
Koninklijke Nederlandse Akademie van Wetenschappen	CVON 2017-20, CVON 2011-19
Spark-Holding BV	2015B002
Directorate for Geosciences	GSE13985
Institute for Translational Neuroscience	REPROGRAM, EPIMAC
Seventh Framework Programme
Cancer Research UK	C20953/A18644
European Commission
Fondation Leducq	16CVD-01
ZonMw	91615052
Academisch Medisch Centrum
Horizon 2020

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.10.092

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Baardman, J., Verberk, S. G. S., Prange, K. H. M., van Weeghel, M., van der Velden, S., Ryan, D. G., Wüst, R. C. I., Neele, A. E., Speijer, D., Denis, S. W., Witte, M. E., Houtkooper, R. H., O'neill, L. A., Knatko, E. V., Dinkova-Kostova, A. T., Lutgens, E., de Winther, M. P. J., & 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

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title = "A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia",

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. The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those “foam cell” macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage 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

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T1 - A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

AU - Baardman, Jeroen

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

PY - 2018/11/20

Y1 - 2018/11/20

N2 - 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. The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those “foam cell” macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage function.

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. The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those “foam cell” macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage function.

KW - atherosclerosis

KW - cardiovascular disease

KW - foam cells

KW - hypercholesterolemia

KW - immunometabolism

KW - inflammation

KW - macrophages

KW - meta-inflammation

KW - metabolic disease

KW - Nrf2

KW - pentose phosphate pathway

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DO - 10.1016/j.celrep.2018.10.092

M3 - Article

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SN - 2211-1247

VL - 25

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JO - Cell Reports

JF - Cell Reports

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ER -

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Abstract

Funding

Keywords

UN SDGs

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