Metabolic reprograming in macrophage polarization

Abstract

Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect.

Keywords: HIF; PGC-1β; glycolysis; macrophage; metabolism.

Figure 1

Metabolic profile of an M1 macrophage is shown. Classically activated macrophages induce an aerobic glycolytic program that results in lactate production and increased levels of intermediates of the Krebs cycle. The HIF1α transcription factor also becomes activated and can drive production of pro-inflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of ROS and NO, and inflammation, which occurs via cytokine production. G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; R5P, ribulose-5-phosphate; S7P, sedoheptulose phosphate; NO, nitric oxide; ROS, reactive-oxygen species.

Figure 2

Metabolic profile of an M2 macrophage is shown. Alternatively activated macrophages trigger a metabolic program including the electron transport chain as well as fatty acid β-oxidation, which is orchestrated by STAT6 and PGC-1β. Arg1 also drives the production of polyamines and ornithine. The key functional consequences are tissue repair and anti-parasitic responses.