Systemic and cellular consequences of macrophage control of iron metabolism

Abstract

Iron is necessary for both mammalian cells and microorganisms, which fiercely compete for this essential nutrient. Accordingly, macrophages exploit the denial of iron from microbial pathogens as an important strategy to accomplish their key role in innate immunity and host defense. Macrophages employ multiple mechanisms to accumulate iron and thus contain microbial infections, but this may come at a price. In particular, at the systemic level iron sequestration in the reticuloendothelial cells can lead to the development of anemia of chronic disease. At the local level, iron sequestration in macrophages, which is targeted to extracellular invaders, can in turn favor intracellular pathogens. Moreover, iron accumulation can per se promote pro-inflammatory activation of macrophages and consequently contribute to maintain the process of inflammation, without resolution. Finally, the peculiar iron trafficking that characterizes alternatively polarized macrophages can influence neighboring cells in the microenvironment and impact on the resolution phase of inflammation. In this review, we describe the role of macrophages in iron metabolism in the context of host defense and iron balance.

Introduction

Most life forms have exploited the useful chemical characteristics of iron for evolving enzymes and proteins involved in fundamental biologic functions, such as oxygen transport, DNA synthesis, energy production. Indeed, iron is an essential nutrient for both higher organisms and microorganisms, the latter having evolved various sophisticated mechanisms for scavenging iron from the environment. On the other side of the battlefield over iron, macrophages, which are key cells of the innate immunity response, are important players in the control of this strategic resource, the so-called nutritional immunity. The key role of iron in host–pathogen interactions is underscored by the evidence that both iron levels and infection–inflammation control hepcidin, “the iron hormone” (see Section 2).

In this review we will cover the major aspects of the connection between iron and macrophages. Recent evidence suggests that iron handling is profoundly different in macrophages depending upon their activation profile [1], [2]. This can range from classical (or M1) activation, typically observed in inflammatory conditions and in response to pathogen challenge, to alternative (or M2) activation, which is driven by immune signals including IL-4/IL-13, TGFβ and glucocorticoids and characterizes the resolution phase of inflammation. Finally, although this review is focused on macrophages, it should be remembered that lymphocytes also require iron for proliferation, as shown by upregulation of TfR1 levels in activated lymphocytes.