The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis

Abstract

Iron is an essential mineral needed for normal physiologic processes. While its function in oxygen transport and other important physiologic processes is well known, less is understood about its role in inflammatory diseases such as atherosclerosis. Existing paradigms suggest iron as a driver of atherosclerosis through its actions as a pro-oxidant capable of causing lipid oxidation and tissue damage. Recently we and others have identified hemoglobin (Hb) derived iron as an important factor in determining macrophage differentiation and function in areas of intraplaque hemorrhage within human atherosclerosis. Hb associated macrophages, M(Hb), are distinct from traditional macrophage foam cells because they do not contain large amounts of lipid or inflammatory cytokines, are characterized by high levels of expression of mannose receptor (CD206) and CD163 in addition to producing anti-inflammatory cytokines such as IL-10. Despite the well-known role of iron as an catalyst capable of producing lipid peroxidation through generation of reactive oxygen species (ROS) such as hydroxyl radical, we and others have shown that macrophages in areas of intraplaque hemorrhage demonstrate reduced intracellular iron and ROS which triggers production of anti-inflammatory cytokines as well as genes involved in cholesterol efflux. These data suggest that manipulation of macrophage iron itself may be a promising pharmacologic target for atherosclerosis prevention through its effects on macrophage inflammation and lipid metabolism. In this review we will summarize the current understanding of iron as it relates to plaque inflammation and discuss how further exploration of this subject may lead to new therapies for atherosclerosis.

Inflammation in arterial diseases

“…Conversely, other products of lipid oxidation such as cholesteryl 9 oxononanoate, docosahexaenoic acid and sphingosin‐1‐phosphate were shown to enhance M2 differentiation that is characterized by increased production of IL‐10, arginase‐1 and mannose receptor . Furthermore, haemoglobin/haptoglobin complex and the clearance of iron were shown to induce alternative M2 macrophage, so called Mhem, characterized by enhanced cholesterol efflux ability and decrease generation of reactive oxygen species (ROS) . Furthermore, macrophage plasticity recently demonstrated additional unexpected properties.…”

Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl‐p53 pathway

“…When hepcidin level is abnormally low, iron overload occurs due to increased FPN‐mediated iron efflux from storage. Excess serum iron increases the level of hepcidin, thus inducing FPN degradation and reducing iron release into the bloodstream 1, 2…”

A transcriptional perspective on human macrophage biology

“…Macrophages are a significant resident cellular component of most tissues, occupying precise anatomical niches especially proximal to the vasculature and epithelia [1][2][3]. In homeostasis, resident macrophages are actively involved in tissue integrity, through the removal of dead cells and debris and regeneration [4], and in physiological processes such angiogenesis [5,6], lipid homeostasis [7][8][9][10], or iron homeostasis [10][11][12][13]. Their numbers increase significantly through recruitment and extravasation in response to chemoattractants secreted locally in response to a wide range of pro-inflammatory sterile and non-sterile stressors.…”