A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

• DOI: 10.1016/j.celrep.2018.10.092
• Publication Date: 2018-11-20T15:42:05Z
• Authors: Jeroen Baardman; Sanne G.S. Verberk; Koen H.M. Prange; Michel van Weeghel; Saskia van der Ve...; Dylan G. Ryan; Rob C.I. Wüst; Annette E. Neele; Dave Speijer; Simone W. Denis; Maarten E. Witte; Riekelt H. Houtko...; Luke A. O’neill; Elena V. Knatko; Albena T. Dinkova...; Esther Lutgens; Menno P.J. de Win...; Jan Van den Bossche
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; QH301-705.5; NF-E2-Related Factor 2; Meta-inflammation; immunometabolism; Citric Acid Cycle; Hypercholesterolemia; pentose phosphate pathway; 610; Metabolic disease; Nrf2; Pentose Phosphate Pathway; 03 medical and health sciences; SDG 3 - Good Health and Well-being; cardiovascular disease; name=General Biochemistry,Genetics and Molecular Biology; 616; Animals; Biology (General); Foam cells; Pentose phosphate pathway; Inflammation; /dk/atira/pure/subjectarea/asjc/1300/1300; Immunometabolism; hypercholesterolemia; Macrophages; meta-inflammation; Atherosclerosis; Cardiovascular disease; metabolic disease; foam cells; macrophages; 3. Good health; Mice, Inbred C57BL; inflammation; Female; atherosclerosis; Glycolysis

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.