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Apolipoprotein E deficiency leads to the polarization of splenic macrophages towards M1 phenotype by increasing iron content

Genes & Immunity (2024)Cite this article

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Abstract

Apolipoprotein E (ApoE) plays a crucial role in iron homeostasis in the body, while macrophages are the principal cells responsible for handling iron in mammals. However, it is unknown whether ApoE can affect the functional subtypes and the iron handling capacity of splenic macrophages (SM). Here, we investigated the effects of ApoE deficiency (ApoE−/−) on the polarization and iron content of SM and its potential mechanisms. ApoE−/− was found to induce a significant increase in the expressions of M1 marker genes CD86, IL-1β, IL-6, IL-12, TNF-α and iNOS and a reduction in M2 marker genes CD206, Arg-1, IL-10 and Ym-1 in SM of mice aged 28 weeks, Meanwhile, ApoE−/− caused a significant increase in iron content and expression of ferritin, transferrin receptor 1 (TfR1), iron regulatory protein 1 (IRP1) and heme oxygenase-1 (HO-1) and a reduction in ferroportin1 (Fpn1) in spleen and/or SM of mice aged 28 weeks. It was concluded that ApoE−/− can increase iron content through increased iron uptake mediated by TfR/ IRPs and decreased iron release mediated by Fpn1, leading to polarization of the SM to M1 phenotype.

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Fig. 1: Effects of ApoE deficiency on spleen size and color, spleen weight, body weight, iron content, and iron levels in splenic macrophages.
Fig. 2: ApoE deficiency up-regulated the expression of Ft-L, Ft-H and TfR1, and down-regulated the expression of Fpn1 in the splenic macrophages.
Fig. 3: ApoE deficiency up-regulated IRPs, Nrf2 and HO-1 protein but not hepcidin mRNA expression in splenic macrophages.
Fig. 4: ApoE deficiency led to the polarization of splenic macrophages towards M1 phenotype.
Fig. 5: ApoE deficiency up-regulated the expression of IL-1β, IL-6, IL-12, TNFα, and iNOS and ROS production and downregulated the expression of IL-10, Arg-1, and Ym-1 in splenic macrophages.
Fig. 6

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The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

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Acknowledgements

We would like to thank Christopher Qian of the Chinese University of Hong Kong for assisting with the preparation and English revision of this manuscript.

Funding

The studies in our laboratories were supported by the National Natural Science Foundation of China (82003702, 31571195).

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Author notes

  1. Meng-Qi Shen

    Present address: School of Health Medicine, Nantong Polytechnic College, Nantong, China

Authors and Affiliations

  1. Institute of Translational and Precision Medicine, Nantong University, Nantong, Jiangsu, China

    Meng-Qi Shen, Wei Li & Zhong-Ming Qian

  2. School of Medicine, Shanghai University, Shanghai, China

    Qian Guo

  3. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China

    Zhong-Ming Qian

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Contributions

Meng-Qi Shen: Conceptualization, Formal analysis, Methodology, Writing—original draft. Qian Guo: Conceptualization, Methodology, Supervision, Writing—review & editing. Wei Li: Conceptualization, Formal analysis, Methodology, Visualization, Writing—original draft. Zhong-Ming Qian: Conceptualization, Methodology, Supervision, Writing—review & editing. All authors read and approved the final manuscript.

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Correspondence to Qian Guo or Zhong-Ming Qian.

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All animal care and experimental protocols in this study were performed according to the Animal Management Rules of the Ministry of Health of China, and approved by the Animal Ethics Committees of Nantong University (NSFC31571195). All mice were sacrificed at 28 weeks old for the designed measurements.

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Shen, MQ., Guo, Q., Li, W. et al. Apolipoprotein E deficiency leads to the polarization of splenic macrophages towards M1 phenotype by increasing iron content. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00290-7

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