Abstract
Macrophages are an integral part of the mononuclear phagocyte system that is critical for maintaining immune homeostasis. They play a key role for initiation and modulation of immunological responses in inflammation and infection. Moreover, macrophages exhibit a wide spectrum of tissue-specific phenotypes in steady-state and pathophysiological conditions. Recent clinical and experimental evidence indicates that the ubiquitous compound heme is a crucial regulator of these cells, e.g., in the differentiation of monocytes to tissue-resident macrophages and/ or in activation by inflammatory stimuli. Notably, heme, an iron containing tetrapyrrole, is essential as a prosthetic group of hemoproteins (e.g., hemoglobin and cytochromes), whereas non-protein bound free or labile heme can be harmful via pro-oxidant, pro-inflammatory, and cytotoxic effects. In this review, it will be discussed how the complex interplay of heme with macrophages regulates homeostasis and inflammation via modulating macrophage inflammatory characteristics and/ or hematopoiesis. A particular focus will be the distinct roles of intra- and extracellular labile heme and the regulation of its availability by heme-binding proteins. Finally, it will be addressed how heme modulates macrophage functions via specific transcriptional factors, in particular the nuclear repressor BTB and CNC homologue (BACH)1 and Spi-C.
Highlights
Macrophages, white blood cells named after their ability to phagocytose, belong to the mononuclear phagocyte system and play a vital role in maintaining immune homeostasis by ingesting and killing pathogens, as well as clearing up dead cells and debris [1]
Retinoic acid-mediated signaling in peritoneal macrophages regulates the local response of B1-cells, a subpopulation of B-cells involved in gut humoral immunity [3], receptor activator of NF-κB ligand (RANK-L) modulates signaling in osteoclasts to regulate osteoblast function [4], and granulocyte macrophage colony-stimulating factor (GM-CSF) mediates differentiation of alveolar macrophages in the lung [5]
The majority of heme synthesis occurs in immature red blood cells (RBCs) and only limited heme synthesis occurs in non-erythroid cells [9]
Summary
Macrophages, white blood cells named after their ability to phagocytose, belong to the mononuclear phagocyte system and play a vital role in maintaining immune homeostasis by ingesting and killing pathogens, as well as clearing up dead cells and debris [1]. In addition to their role in immune surveillance, macrophages exhibit heterogeneous organ-specific physiological functions, which are induced and maintained by tissue-specific environmental factors [2]. In pathophysiological conditions, this complex system is critical for regulating the inflammatory phenotype of these cells [18]
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