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

Research output: Contribution to JournalArticleAcademicpeer-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 languageEnglish
Pages (from-to)2044-2052.e5
Number of pages23
JournalCell Reports
Volume25
Issue number8
DOIs
Publication statusPublished - 20 Nov 2018

Keywords

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

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