Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis

Jing Cai,Meng Zhang,Kuanyu Li,Longcheng Shang,Tong Qiao,Huihui Li,Yutong Liu,Tianze Xu,Fudi Wang,Zhipeng Chen

doi:10.1186/s13578-020-00500-5

Abstract

BackgroundMacrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques. Although iron deposition was found in human atherosclerotic plaques, clinical and pre-clinical studies showed controversial results. Several epidemiological studies did not show the positive correlation between a systemic iron status and an incidence of cardiovascular diseases, suggesting that the iron involvement occurs locally, rather than systemically.ResultsTo determine the direct in vivo effect of iron accumulation in macrophages on the progression of atherosclerosis, we generated Apoe−/− mice with a macrophage-specific ferroportin (Fpn1) deficiency (Apoe−/−Fpn1LysM/LysM). Fpn1 deficiency in macrophages dramatically accelerated the progression of atherosclerosis in mice. Pathophysiological evidence showed elevated levels of reactive oxygen species, aggravated systemic inflammation, and altered plaque-lipid composition. Moreover, Fpn1 deficiency in macrophages significantly inhibited the expression of ABC transporters (ABCA1 and ABCG1) by decreasing the expression of the transcription factor LXRα, which reduced cholesterol efflux and therefore promoted foam cell formation and enhanced plaque formation. Iron chelation relieved the symptoms moderately in vivo, but drastically ex vivo.ConclusionsMacrophage iron content in plaques is a critical factor in progression of atherosclerosis. The interaction of iron and lipid metabolism takes place in macrophage-rich atherosclerotic plaques. And we also suggest that altering intracellular iron levels in macrophages by systemic iron chelation or dietary iron restriction may be a potential supplementary strategy to limit or even regress the progression of atherosclerosis.

Highlights

Macrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques
Macrophage‐specific ferroportin 1 (Fpn1) deficiency drastically promotes atherosclerosis progression To determine the role of macrophage iron accumulation in the development of atherosclerosis, we crossed Fpn1LysM/LysM mice [21] with Apoe−/− mice to generate Apolipoprotein E-deficient (Apoe−/−)Fpn1LysM/LysM mice, in which Fpn1 was deleted in macrophages on the genetic background of global Apoe knockout
The Oil Red O-stained area in aortic roots presented more lipid content in Apoe−/−Fpn1LysM/LysM mice than in Apoe−/− mice (Fig. 1e, f ). These results demonstrate that the Fpn1 deletioninduced iron accumulation in plaque macrophages is associated with the severe atherosclerosis

Summary

Introduction

Macrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques. The iron concentration is higher in human atherosclerotic plaques than in healthy arterial tissue [9], it is still unclear whether iron accumulation in atherosclerotic plaques is a cause or a consequence, whether iron deposition is deleterious, and whether the associated harmful effects are cell specific [10]. Considering the key roles of macrophages in the formation and progression of atherosclerotic plaques, combined with the fact that macrophages provide a large amount of iron in the circulation to meet systemic requirements by recycling iron from senescent red blood cells [11], selective iron deposition in macrophages has been proposed as a mechanism underlying accelerated atherosclerosis progression via catalytic generation of reactive oxygen species (ROS) and promotion of foam cell formation [12, 13]. Several mouse models of iron overload (i.e., high-iron diet or injection with irondextran [14, 15] and hereditary hemochromatosis (HH) [16,17,18] characterized by systemic iron overload rather than macrophage-specific iron deposition are likely not suitable to integrate the current data for elucidating the impact of iron on atherosclerosis

Methods

Results

Discussion

Conclusion