New insights into the role of iron in inflammation and atherosclerosis

Abstract

Iron is fundamental for life-essential processes. However, it can also cause oxidative damage, which is thought to trigger numerous pathologies, including cardiovascular diseases. The role of iron in the pathogenesis of atherosclerosis is still not completely understood. Macrophages are both key players in the handling of iron throughout the body and in the onset, progression and destabilization of atherosclerotic plaques. Iron itself might impact atherosclerosis through its effects on macrophages. However, while targeting iron metabolism within macrophages may have some beneficial effects on preventing atherosclerotic plaque progression there may also be negative consequences. Thus, the prevailing view of iron being capable of accelerating the progression of coronary disease through lipid peroxidation may not fully take into account the multi-faceted role of iron in pathogenesis of atherosclerosis. In this review, we will summarize the current understanding of iron metabolism in the context of the complex interplay between iron, inflammation, and atherosclerosis.

Keywords: Atherosclerosis; Hepcidin-ferroportin axis; Intraplaque haemorrhage; Iron metabolism; Macrophages.

Fig. 1

Systemic iron regulation. Iron is absorbed in the duodenum and upper jejunum. Elemental iron is taken up from the intestinal lumen via divalent metal transporter 1 (DMT1). High systemic iron levels lead to increased hepcidin expression in the liver. Hepcidin binds ferroportin, leading to its internalization and degradation with subsequent drop of systemic serum iron, but an increase in intracellular free iron levels. Accordingly, hepcidin levels are decreased in iron deficiency, which increases iron absorption and cellular iron release.

Fig. 2

Intraplaque haemorrhage in fibroatheroma with a core in a late stage of necrosis (Panels A, B, C, D, and E) and thin-cap fibroatheroma (panels F, G, H, I, and J). Panel A shows a low-power view of a fibroatheroma with a late-stage necrotic core (NC) (Movat pentachrome, ×20). Panel B shows intense staining of CD68-positive macrophages within the necrotic core (×200). Panel C shows extensive staining for glycophorin A in erythrocyte membranes localized with numerous cholesterol clefts within the necrotic core (×200). Panel D shows iron deposits (blue pigment) within foam cells (Mallory's stain, ×200). Panel E shows microvessels bordering the necrotic core with perivascular deposition of von Willebrand factor (vWF) (×400). Panel F shows a low-power view of a fibroatheroma with a thin fibrous cap (arrow) overlying a relatively large necrotic core (Movat pentachrome, ×20). The fibrous cap is devoid of smooth-muscle cells (not shown) and is heavily infiltrated by CD68-positive macrophages (Panel G, ×200). Panel H shows intense staining for glycophorin A in erythrocyte membranes within the necrotic core, together with cholesterol clefts (×100). Panel I shows an adjacent coronary segment with iron deposits (blue pigment) in a macrophage-rich region deep within the plaque (Mallory's stain, ×200). Panel J shows diffuse, perivascular deposits of von Willebrand factor in microvessels, indicating that leaky vessels border the necrotic core (×400). Reproduced with permission from Kolodgie FD et al. N Engl J Med 2003; 349:2316–2325. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Intraplaque haemorrhage. Fragile and permeable intraplaque vasa vasorum drive haemorrhage inside the plaque. The pro-oxidant environment of the plaque promotes haemolysis as well as the formation of cholesterol crystals. Free iron from haemoglobin might further catalyse these reactions. Haptoglobin binds free haemoglobin, and haemoglobin:haptoglobin complexes are cleared via CD163+ macrophages. These M(Hb) macrophages have been associated with plaque progression, microvascularity, and upregulation of hypoxia inducible factor-1α (HIF-1α).

Fig. 4

Effect of hepcidin on macrophages phenotype and function in the setting of atherosclerosis. Hepcidin may play different roles in atherogenesis depending upon the stage of atherosclerosis. a) In early and mid-stage plaques, M1 Macrophages are predominant. Hepcidin induces degradation of FPN, leading to an increase of intracellular iron in macrophages. Intracellular iron accumulation results in an increased ox-LDL cholesterol incorporation via scavenger receptors such as CD36 and LOX-1 (LDL receptor-1), and increased inflammatory (LPS-stimulated) signalling through via TLR-4, decreasing cholesterol efflux, and intracellular reactive oxygen species (ROS) generation. Overall, these cells exhibit a phenotype consistent with pro-inflammatory foamy macrophage phenotype. Under these conditions, macrophages contribute to atherosclerosis progression. In an environment with only low or without hepcidin, intracellular iron is actively exported out of the macrophages via FPN. Lowering intracellular iron within the macrophage suppresses LDL uptake and increases its export via ABCA1 and ABCG1, lowers TLR-4-dependent inflammatory signalling and ROS production. These effects are thought to be anti-atherogenic. b) In advanced plaques with intraplaque haemorrhage, M(Hb) Macrophages are abundant. Iron is an essential cofactor for PHD that mediates degradation of HIF 1α. Low iron levels promote nuclear translocation of HIF-1α, promoting VEGF target gene expression and leading to further intraplaque angiogenesis, endothelial permeability, and inflammatory signalling. Thus, in early- to mid-stage plaques, inhibition of hepcidin may have beneficial effects by restraining the effects of pro-inflammatory macrophages, while in late stage lesions (i.e. those with IPH), lowering of macrophage iron may promote plaque progression through VEGF-mediated increases in angiogenesis, permeability, and inflammatory cells recruitment.