Ironing Out the Details: How Iron Orchestrates Macrophage Polarization

Abstract

Iron fine-tunes innate immune responses, including macrophage inflammation. In this review, we summarize the current understanding about the iron in dictating macrophage polarization. Mechanistically, iron orchestrates macrophage polarization through several aspects, including cellular signaling, cellular metabolism, and epigenetic regulation. Therefore, iron modulates the development and progression of multiple macrophage-associated diseases, such as cancer, atherosclerosis, and liver diseases. Collectively, this review highlights the crucial role of iron for macrophage polarization, and indicates the potential application of iron supplementation as an adjuvant therapy in different inflammatory disorders relative to the balance of macrophage polarization.

Keywords: epigenetics; inflammation; iron; macrophage; metabolism.

Figure 1

Cellular pathways whereby iron shapes macrophage polarization. Iron deprivation may suppress NF-κB activation to block M1-like macrophage polarization (A). In some special cases, iron deprivation could lower the activity of Nox to promote p65 nuclear translocation and increases NF-κB activity, promoting M1-like macrophage polarization (B). Iron treatment could activate MAPK-p-MK2 pathway to increase TNF-α production to generate a large amount of OH• and ONOO•, promoting M1-like macrophage polarization (C). Acute iron deprivation inhibits ATF4 expression to suppress M2-like macrophage polarization in tumorous tissues (D). Iron treatment may promote M1-like macrophage polarization by inducing the activation of MAPK, NF-κB and other proinflammatory signaling pathways via increasing the production of intracellular ROS (E). Iron overload increases hepcidin expression which can inhibit STAT6 activation while promote IRF3 expression to increase iNOS expression in M1-like macrophages (F). Iron can activate NLRP3 inflammasome to promote M1-like macrophage polarization by the generation of ROS (G). Iron might enhance M2-like macrophage polarization through moderately activating of mtROS cascading with NF-κB pathway by down-regulating GMFG level (H). ATF4, activating transcription factor 4; GMFG, glia maturation factor-γ; IRF3, interferon regulatory factor 3; MAPK, mitogen-activated protein kinase; MK2, kinase 2; NF-κB, nuclear factor κB; NLRP3, NOD‐like receptor; Nox, NADPH oxidase; ROS, reactive oxygen species; STAT6, signal transducer and activator of transcription 6. “↑”, increase; “↓”, decrease. Question mark means that the mechanism needs experimental confirmation.

Figure 2

Mechanisms associated with metabolic pathways whereby iron shapes macrophage polarization. Iron deprivation directly inhibits the expression of NDUFS6 and SDHB and blocks the activity of mitochondrial aconitase to cause citrate accumulation, thereby switching resting macrophages towards M1-like macrophages (A). Iron deprivation limits M1 polarization by increasing itaconate:succinate ratio through altering metabolic fluxes and inducing TGF-β signaling pathway (B). Specially, iron deprivation decreases histone acetylation to reduce transcription of the nuclear DNA-encoded OXPHOS genes, suppressing M2-like phenotype (C). Iron-load increases the expressions of glycolysis-related genes to promote glycolysis in macrophages, enhancing M1-like macrophage polarization (D). Iron might restrain M2-like macrophage, while favors M1-like macrophage polarization via reducing the expression of NDUFV2 and SDHD (E), and SOD1 and SOD2 through down-regulating GMFG (F), respectively. OXPHOS, oxidative phosphorylation; TGF-β, transforming growth factor-β. “↑”, increase; “↓”, decrease. Question mark means that the mechanism needs experimental confirmation.

Figure 3

Mechanisms associated with epigenetic regulation/modification whereby iron shapes macrophage polarization. Iron supplementation may reduce miR-29a expression to block the activation of SOCS1/STAT6 signal pathway, inhibiting TAM polarization (A). Iron could promote M1-like macrophage polarization by increasing miR-214 expression (B). Iron could increase the enzyme activity of JMJD3 to demethylate H3K27me3, relieving the transcriptional silencing of LPS-induced genes and facilitating M1-like macrophage polarization (C). Iron might promote macrophages toward pro-inflammatory phenotype through demethylating H4K20me3 by enhancing the enzyme activity of HR23A (D). Iron deficiency might cause the loss of H3K9Ac and H3K4me3 to reduce hepcidin expression, inhibiting M1-like macrophage polarization (E). Iron deficiency inhibits M1 activation (e.g., pro-inflammatory responses) possibly through increasing HDAC1 binding to the related genes (F). Iron deficiency inhibits M1-like phenotype by lowering hepcidin expression via enhancing HDAC3 binds chromatin at the hepcidin locus (G). H3K27me3, histone 3 lysine 27 trimethylation; H4K20me3, histone 4 lysine 20 trimethylation; HDAC, histone deacetylase; SOCS1, suppressor of cytokine signaling 1. “↑”, increase; “↓”, decrease. Question mark means that the mechanism needs experimental confirmation.