Editors' ChoiceIRON METABOLISM

Casting the development of iron-recycling macrophages

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Science Translational Medicine  22 Apr 2020:
Vol. 12, Issue 540, eabb5674
DOI: 10.1126/scitranslmed.abb5674

Abstract

Interleukin-33 signaling directs the maturation of iron-metabolizing macrophages.

The regulation of iron homeostasis at the tissue and cellular level is essential to maintain vital physiological processes, including erythropoiesis (red blood cell production) and oxygen transport. Alterations in iron metabolisms and recycling from senescent red blood cells can result in disease states. Although iron deficiency is the main cause of anemia, excessive iron accumulation from hemochromatosis may damage organs including the liver, pancreas, brain, and heart. Defective iron metabolism may also be involved in atherosclerotic cardiovascular disease. Major knowledge gaps remain, including how plaque macrophages regulate iron clearance after intraplaque hemorrhage. Therefore, the identification of regulatory signaling that controls the development of iron-recycling macrophages is a key first step to dissect tissue-specific pathophysiological functions.

In this study, Lu et al. performed a series of elegant in vitro and in vivo mouse studies to reveal how interleukin (IL)-33, a member of the IL-1 cytokine family that is constitutively expressed in the nucleus of epithelial and endothelial cells, directs the differentiation of pre–red pulp macrophages into mature iron-recycling macrophages. They show that IL-33 released by damaged erythrocytes instructs the maturation of iron-metabolizing macrophages through the activation of the IL-33 receptor IL1RL1 and downstream activation of myeloid differentiation primary response 88 (MyD88) adaptor protein and extracellular signal–regulated kinases 1 and 2 (ERK1/2). IL-33 signaling sustains the activation of the transcriptional regulator of myelopoiesis GATA2 and the expression of GATA2 target genes. The authors were unable to elucidate how IL-33 is maintained and stored in enucleated erythrocytes and the role of IL1RL1 in the bone marrow; these questions will need to be addressed in future studies.

Lu et al.’s results provide insight on key signaling pathways involved in the development of iron-handling macrophages. Iron metabolism is fundamental to maintaining tissue homeostasis; therefore, understating the sensing mechanisms that induce the differentiation of iron-recycling macrophages offers promising strategies for several diseases. For example, the validation of this pathway in experimental models of atherosclerosis could provide a step forward in understanding the causal role of plaque iron-metabolizing macrophages in disease progression and potential therapeutic strategies for cardiovascular disease.

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