Time and Demand are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway

Abstract

A process is a function of time; in immunometabolism, this is reflected by the stepwise adaptation of metabolism to sustain the bio-energetic demand of an immune-response in its various states and shades. This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation. We then focus on the process of macrophage activation and aim to delineate the factor time within the current molecular context of metabolic-rewiring important for adapting primary carbohydrate metabolism. In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand. We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

Metabolic regulation of macrophage phenotype and function

“…Collectively, the above evidences suggest that in myeloid cells, glycolysis is a central mediator of inflammatory and microbicidal phenotype . Although glycolysis is an energy inefficient pathway for generation of ATP (2 ATP molecules per unit of glucose as compared to 36 ATP by TCA cycle and OXPHOS), it is a rapid way to generate energy, cofactors for enzymatic reactions (NADH from reduction of NAD+) and biosynthetic intermediates for synthesis of nucleotides, amino acids and fatty acids, all of which are required for their effector functions . High glycolytic rates allow M1 macrophages to produce sufficient energy and biosynthetic intermediates rapidly for quick execution of microbicidal and effector activities to control infection.…”

Metabolomics in rheumatic diseases: desperately seeking biomarkers

“…The PPP enables glycolytic cells to meet their anabolic demands and combat oxidative stress. A glycolysis–PPP axis is also involved in M1 macrophage polarization 178 .…”

HIF-2α in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis

“…Although HIF isoforms regulate overlapping functions, they also control independent and potentially counteracting pathways (63). For example, HIF-1α uniquely regulates the Mϕ “M1” polarization phenotype (18) (64) (65), in part through HIF-1α control of glycolytic enzyme expression and the glucose transporter GLUT-1 (66, 67). In contrast, HIF-2α appears to act independent of glycolytic control, instead focused to endotoxin-induced cytokine production (19).…”