@article{e834de9fb9f44599b73fbffeb653942e,
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.",
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",
note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = nov,
day = "20",
doi = "10.1016/j.celrep.2018.10.092",
language = "English (US)",
volume = "25",
pages = "2044--2052.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}