The Macrophage Iron Signature in Health and Disease

Abstract

Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.

Keywords: disordered iron metabolism; iron metabolism; macrophage polarization.

Figure 1

Hypothetical scheme of MΦ iron polarization during injury and recovery. Different MΦ subpopulations have been described with varying levels of lymphocyte antigen 6 (Ly6C) and major histocompatibility complex (MHCII). Under physiological conditions, resident MΦ predominate together with embryonic progenitors that are not replenished by circulating monocytes under steady-state conditions. Resident MΦ in the healthy state promote tissue homeostasis. CCR2⁺ MΦ are replenished by blood monocyte recruitment and local proliferation, whereas CCR2⁻ MΦ are repopulated by local proliferation. Infiltrating pro-inflammatory monocyte-derived MΦ (Ly6C⁺ CCR2⁻ and Ly6C⁺ CCR2⁺) promote tissue injury and death by substitution of the resident MΦ subpopulation. Shown is a continuum of functional activation states, with two extreme phenotypes linked to the highly diverse MΦ functional activation states in the different stages of inflammation and resolution of inflammation. The iron phenotype is also closely related to the MΦ polarization profile, with its two extremes of iron retention and iron release.