Insufficient Iron Improves Pristane-Induced Lupus by Promoting Treg Cell Expansion

Gao, Xiaofei; Song, Yang; Lu, Shuang; Hu, Longyuan; Zheng, Meiling; Jia, Sujie; Zhao, Ming

doi:10.3389/fimmu.2022.799331

Cited by 4 publications

(3 citation statements)

References 41 publications

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“…Consistent with our findings, this was linked to modulation of T reg (Gao et al, 2022a ), T H 17 (Teh et al, 2021 ), and FT H (Gao et al, 2022b ) cells and was associated with regulation of DNA demethylation (Gao et al, 2022b ; Teh et al, 2021 ). However, whether regulation of Fe metabolism in T reg cells affects systemic lupus erythematosus was, to the best of our knowledge, not established (Gao et al, 2022a ).…”

Section: Discussionsupporting

confidence: 89%

“…8D ), likely originating from auto-reactive T N cells and/from ex-T reg cells that lost Foxp3 expression to become inflammatory and presumably pathogenic (Bailey-Bucktrout et al, 2013 ). This is consistent with regulation of Fe metabolism modulating the incidence and severity of autoimmune conditions, as demonstrated for systemic lupus erythematosus (Gao et al, 2022a ). Consistent with our findings, this was linked to modulation of T reg (Gao et al, 2022a ), T H 17 (Teh et al, 2021 ), and FT H (Gao et al, 2022b ) cells and was associated with regulation of DNA demethylation (Gao et al, 2022b ; Teh et al, 2021 ).…”

Section: Discussionsupporting

confidence: 89%

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Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Wu,

Carlos,

Braza

et al. 2024

EMBO J

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Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten–eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Wu,

Carlos,

Braza

et al. 2024

EMBO J

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“…In animal models of iron deficiency, lymphocyte function is severely impaired, and the immune response to immunisation and viral infection is inhibited [20,21]. Similarly, iron deficiency decreases inflammation and improves outcomes in mouse models of autoimmune disease [22][23][24][25]. In humans, associations between iron deficiency and attenuated responses to some vaccines have been observed [20,21,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Cellular iron governs the host response to malaria

Wideman,

Frost,

Richter

et al. 2023

PLoS Pathog

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Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

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Essential Trace Element Status in Systemic Lupus Erythematosus: a Meta-analysis Based on Case-Control Studies

Wang

Huang

et al. 2022

Biol Trace Elem Res

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Insufficient Iron Improves Pristane-Induced Lupus by Promoting Treg Cell Expansion

Cited by 4 publications

References 41 publications

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Cellular iron governs the host response to malaria

Essential Trace Element Status in Systemic Lupus Erythematosus: a Meta-analysis Based on Case-Control Studies

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