Cellular Metabolism and Macrophage Functional Polarization

Abstract

Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.

Thyroid hormone metabolism in innate immune cells

“…They are also capable of antigen presentation and can 232:2 elicit a T-cell response (Hume 2008). M1 polarization is accompanied by changes in cellular metabolism, shifting towards enhanced glycolysis (Freemerman et al 2014, Galvan-Pena & O'Neill 2014, Zhu et al 2015. Essential components of adequate pro-inflammatory macrophage function are phagocytosis, the generation of ROS by NADPH oxidase and the generation of reactive nitrogen species (RNS), which is mediated by inducible nitric oxide synthase (iNOS) (Weiss & Schaible 2015).…”

“…M2 macrophages are tolerogenic and immunomodulatory cells that are involved in wound healing and tissue remodelling (Murray & Wynn 2011). This is also accompanied by metabolic changes resulting in enhanced fatty acid oxidation and mitochondrial oxidative phosphorylation (Vats et al 2006, Galvan-Pena & O'Neill 2014, Zhu et al 2015. More recent data suggest that macrophage polarization is not as clear cut as these two phenotypes and represents more of a spectrum ranging from pro-to anti-inflammatory (Hume 2015).…”

Role of metabolism during viral infections, and crosstalk with the innate immune system

“…However, they found an increase in the levels of pyruvate, suggesting that either this comes as an effect of a down-regulation of the TCA cycle, or is a de novo synthesis of pyruvate through other sources (amino acid oxidation). Although it does not exactly follow the model of the Warburg effect in M1 macrophages, or the TCA cycle in M2 macrophages (12), the different source of cells has to be taken in account, and the use of another type of virus (HIV).…”

“…One of the branches of the immune system, innate immunity, is one of the first lines of defence in case of an infection process, and for example, metabolic programmes for polarized macrophages are completely different (12). Given the importance of understanding the players involved during infection, a broad perspective is presented here.…”

The aging immune system and nutritional interventions

“…The tryptophan-degrading enzyme IDO expression is induced by IFN-, but its expression may drive M2 polarization [396]. TNF, in turn, reduces IDO expression [397]. Methionine restriction seems to decrease macrophage migration and infiltration [389].…”