Ironing out Macrophage Immunometabolism

Abstract

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism.

Keywords: inflammation; iron; macrophages; metabolism.

Figure 1

M1 and M2 macrophages represent the extremes of a spectrum. The major properties and functions of polarized macrophages are summarized in the boxes. The differential expression of representative molecules and effectors is also shown.

Figure 2

Schematic diagram of different tryptophan metabolism pathways. According to results found in T cells lacking tetrahydrobiopterin (BH4) (see text), it is conceivable that the conversion of tryptophan by tryptophan mono-oxygenase results in high iron levels and efficient mitochondrial activity, whereas the kynurenine pathway initiated by IDO1 activity leads to the formation of the iron chelator picolinic acid.

Figure 3

Alternative pathways of cis-aconitate metabolism. Iron availability and reactive molecules produced under inflammatory condition like nitric oxide (NO) can target the iron-sulfur cluster and alter aconitase activity, thus affecting the amount of cis-aconitate available for the decarboxylating activity of CAD/Irg1 and the production of itaconate.