“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels

Abstract

Macrophages reside in virtually every organ. First arising during embryogenesis, macrophages replenish themselves in the adult through a combination of self-renewal and influx of bone marrow-derived monocytes. As large phagocytic cells, macrophages participate in innate immunity while contributing to tissue-specific homeostatic functions. Among the key metabolic tasks are senescent red blood cell recycling, free heme detoxification, and provision of iron for de novo hemoglobin synthesis. While this systemic mechanism involves the shuttling of iron between spleen, liver, and bone marrow through the concerted function of defined macrophage populations, similar circuits appear to exist within the microenvironment of other organs. The high turnover of iron is the prerequisite for continuous erythropoiesis and tissue integrity but challenges macrophages’ ability to maintain cellular iron homeostasis and immune function.This review provides a brief overview of systemic, microenvironmental, and cellular aspects of macrophage iron handling with a focus on exciting and unresolved questions in the field.

Anaemia, iron homeostasis and pulmonary hypertension: a review

“…Another link between BMPR2 signalling, perivascular inflammation and iron homeostasis is established for the IL6/ signal transducer and activator of transcription 3 (STAT3) pathway [48]. The expression of IL6, a multifunctional proinflammatory cytokine and anti-inflammatory myokine is induced by iron depletion [49]. Vice versa, IL6 stimulates hepcidin expression via the STAT3 pathway thereby causing intracellular iron sequestration [50].…”

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Macrophages (Mɸs), the principal cells responsible for handling iron in mammals, are present in all tissues and are pertinent to tissue homeostatic function (6)(7)(8)(9)(10). Mɸs are highly plastic in response to the tissue niche, acquiring rapid polarization on a spectrum from an M1-like proinflammatory to M2-like tissue repair phenotype (reviewed in refs.…”

Characterisation of subpopulations of chicken mononuclear phagocytes that express TIM4 and the macrophage colony-stimulating factor receptor (CSF1R)

“…The underlying transcriptional regulation is also consistent with data from mice, in that genes encoding known regulators of apoptotic receptors in mice, NR1H33 and PPARG (51) were also strongly-enriched in the chicken Kupffer cells. In mice, Kupffer cells are required for the elimination of senescent red blood cells and recycling of iron (52). Consistent with the conservation of this function and its regulation, the chick Kupffer cells were enriched for expression of the ferriportin gene, SLC40A1 , the haeme transporter, SLC48A1 , ferritin heavy chain, FTH1 and haem oxygenase ( HMOX1 ), and the transcription factor, MAF, which regulates expression of these genes (53) (Table S1).…”