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Regulation of tissue iron homeostasis: the macrophage “ferrostat”
Nathan C. Winn, … , Katrina M. Volk, Alyssa H. Hasty
Nathan C. Winn, … , Katrina M. Volk, Alyssa H. Hasty
Published January 30, 2020
Citation Information: JCI Insight. 2020;5(2):e132964. https://doi.org/10.1172/jci.insight.132964.
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Regulation of tissue iron homeostasis: the macrophage “ferrostat”

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Abstract

Iron is an essential element for multiple fundamental biological processes required for life; yet iron overload can be cytotoxic. Consequently, iron concentrations at the cellular and tissue level must be exquisitely governed by mechanisms that complement and fine-tune systemic control. It is well appreciated that macrophages are vital for systemic iron homeostasis, supplying or sequestering iron as needed for erythropoiesis or bacteriostasis, respectively. Indeed, recycling of iron through erythrophagocytosis by splenic macrophages is a major contributor to systemic iron homeostasis. However, accumulating evidence suggests that tissue-resident macrophages regulate local iron availability and modulate the tissue microenvironment, contributing to cellular and tissue function. Here, we summarize the significance of tissue-specific regulation of iron availability and highlight how resident macrophages are critical for this process. This tissue-dependent regulation has broad implications for understanding both resident macrophage function and tissue iron homeostasis in health and disease.

Authors

Nathan C. Winn, Katrina M. Volk, Alyssa H. Hasty

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Figure 2

Proposed model by which resident iron-handling Mɸs regulate tissue homeostasis during an insult.

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Proposed model by which resident iron-handling Mɸs regulate tissue homeo...
(1) Parenchymal cell injury initiates intracellular transduction signals that propagate transcriptional and nontranscriptional stress signals. (2) Local tissue-resident Mɸs are recruited to the injured site. Since injured cells are more susceptible to iron-induced oxidative damage, Mɸs sequester extracellular iron to decrease iron uptake in the injured parenchymal cell. LIP has been reported to increase in response to cell injury, which may promote iron efflux and Mɸ uptake. (3) A latency period follows, in which the Mɸ retains sequestered iron, allowing for parenchymal cell restoration. This phase of Mɸ iron retention may be aided by release of inflammatory cytokines and/or IFN responses that favor an iron-loaded Mɸ (i.e., suppression of Fpn-mediated iron export). Parenchymal cell repair requires iron for processes such as DNA synthesis. This utilization of parenchymal intracellular iron depletes ferritin stores. (4) The Mɸ mobilizes and relinquishes iron for parenchymal cell repair. (5) An undefined termination signal communicates cell resolution and the Mɸ regresses from the site, completing the homeostatic circuit and maintaining local iron balance.

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