The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

Mu, Qingdian; Chen, Liyun; Gao, Xiangjing; Shen, Shuying; Sheng, Wenjing; Min, Junxia; Wang, Fudi

doi:10.1016/j.scib.2021.02.010

Cited by 95 publications

(64 citation statements)

References 148 publications

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“… 21 We found that 2 injections of hepcidin 19 led to higher levels of both splenic FPN ( Figure 6G-H ; supplemental Figure 11A) and serum iron levels ( Figure 6I ) in the Rnf217 Lysm/Lysm mice compared with hepcidin-treated Rnf217 flox/flox mice, suggesting that hepcidin-mediated FPN degradation is at least partially dependent on RNF217. In addition, the LPS-induced hypoferremia 50 in Rnf217 flox/flox mice was less severe in Rnf217 Lysm/Lysm mice ( Figure 6J ), in part because of reduced FPN degradation ( Figure 6K-L ; supplemental Figure 11B).…”

Section: Resultsmentioning

confidence: 99%

RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Jiang

Wang

et al. 2021

Blood

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Ferroportin (FPN), the body's sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of two different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using two conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases.

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Section: Resultsmentioning

confidence: 99%

RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Jiang

Wang

et al. 2021

Blood

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“…Recent studies have shown that iron homeostasis plays an important role in the regulation of immune responses, and an imbalance in iron homeostasis may affect the development, function, and death of immune cells(48). Ferroptosis has been identified as one of the forms of cell death in a variety of immune cells, affecting the immune response with potential interplay between ferroptosis and the immune response under certain circumstances(49).…”

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confidence: 99%

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

et al. 2021

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Stanford type A aortic dissection (TAAD) is one of the most dangerous vascular diseases worldwide, and the mechanisms of its development remain unclear. Further molecular pathology studies may contribute to a comprehensive understanding of TAAD and provide new insights into diagnostic markers and potential therapeutic targets. Recent studies have identified that ferroptosis, a form of cell death, may play a previously unrecognized role in influencing the development of TAAD. In this study, we explored the pathological role of ferroptosis in TAAD by performing bioinformatics analyses. Gene set enrichment analysis (GSEA) showed that the ferroptosis-related gene (FRG) set was significantly different between normal and TAAD aortic samples at an overall level (p < 0.001). Further Gene Ontology (GO) enrichment analysis found that FRGs may influence the response to oxygen levels, transition metal ion homeostasis, and the response to hypoxia by regulating oxidoreductase activity and post-transcriptional ubiquitination modifications, which may regulate cellular ferroptosis and contribute to the structural abnormalities that render patients susceptible to TAAD. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the HIF-1 signaling pathway may be a key pathway regulating cellular ferroptosis in TAAD development. We further identified six key genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, MYC) from differentially expressed FRGs in TAAD by constructing a protein-protein interaction (PPI) network, all key genes were upregulated in TAAD. Four of the key genes (CA9, IL6, CDKN1A, and HIF1A) were demonstrated to be correlated with cigarette smoke extract-induced ferroptosis in aortic vascular smooth muscle cells. These results suggest that ferroptosis is one of the essential pathological processes in the development of TAAD, and some FRGs affect TAAD development by mediating cellular ferroptosis, which provides deepening insights into the molecular mechanisms and potential therapeutic 3 targets of TAAD.

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“…Both iron deficiency and iron overload can lead to various pathological conditions 23 . The maintenance of iron homeostasis is crucial for the adaptive immune system 30 - 32 . The ROS produced by the Fenton reaction of excessive iron is an important source of cytotoxic ROS in living cells.…”

Section: Discussionmentioning

confidence: 99%

The kinase PDK1 regulates regulatory T cell survival via controlling redox homeostasis

et al. 2021

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Rationale: Regulatory T cells (Treg cells) play an important role in maintaining peripheral tolerance by suppressing over-activation of effector T cells. The kinase PDK1 plays a pivotal role in conventional T cell development. However, whether PDK1 signaling affects the homeostasis and function of Treg cells remains elusive. Methods: In order to evaluate the role of PDK1 in Treg cells from a genetic perspective, mice carrying the floxed PDK1 allele were crossbred with Foxp3 Cre mice to efficiently deleted PDK1 in Foxp3 + Treg cells. Flow cytometry was used to detect the immune cell homeostasis of WT and PDK1 fl/fl Foxp3 Cre mice. RNA-seq was used to assess the differences in transcriptional expression profile of WT and PDK1-deficient Treg cells. The metabolic profiles of WT and PDK1-deficient Treg cells were tested using the Glycolysis Stress Test and Mito Stress Test Kits by the Seahorse XFe96 Analyser. Results: PDK1 was essential for the establishment and maintenance of Treg cell homeostasis and function. Disruption of PDK1 in Treg cells led to a spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number and function of Treg cells. The deletion of PDK1 in Treg cells destroyed the iron ion balance through regulating MEK-ERK signaling and CD71 expression, resulting in excessive production of intracellular ROS, which did not depend on the down-regulation of mTORC1 signaling. Inhibition of excessive ROS, activated MEK-Erk signaling or overload Fe 2+ could partially rescue the survival of PDK1-deficient Treg cells. Conclusion: Our results defined a key finding on the mechanism by which PDK1 regulates Treg cell survival via controlling redox homeostasis.

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The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

Cited by 95 publications

References 148 publications

RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis

The kinase PDK1 regulates regulatory T cell survival via controlling redox homeostasis

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