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

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

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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, 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.",

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

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

year = "2018",

month = nov,

day = "20",

doi = "10.1016/j.celrep.2018.10.092",

language = "English",

volume = "25",

pages = "2044--2052.e5",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "8",

}

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, https://doi.org/10.1016/j.celrep.2018.10.092

TY - JOUR

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.

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.

KW - Nrf2

KW - atherosclerosis

KW - cardiovascular disease

KW - foam cells

KW - hypercholesterolemia

KW - immunometabolism

KW - inflammation

KW - macrophages

KW - meta-inflammation

KW - metabolic disease

KW - pentose phosphate pathway

UR - http://www.mendeley.com/research/defective-pentose-phosphate-pathway-reduces-inflammatory-macrophage-responses-during-hypercholestero

U2 - 10.1016/j.celrep.2018.10.092

DO - 10.1016/j.celrep.2018.10.092

M3 - Article

C2 - 30463003

SN - 2211-1247

VL - 25

SP - 2044-2052.e5

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Abstract

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