Selenium–GPX4 axis protects follicular helper T cells from ferroptosis

Yao, Yin; Chen, Zhian; Zhang, Hao; Chen, Cailing; Zeng, Ming; Yunis, Joseph; Wei, Yunbo; Wan, Yanmin; Wang, Naiqi; Zhou, Mingzhe; Qiu, Chao; Zeng, Quan; Ong, Hong Sheng; Wang, Hao; Makota, F Victor; Yang, Yang; Yang, Zhaohui; Wang, Nan; Deng, Jun; Shen, Chao; Xia, Yan; Lin, Yuan; Lian, Zhaoqin; Deng, Yi‐Ke; Guo, Chongfeng; Huang, Ao; Zhou, Pengcheng; Shi, Haibo; Zhang, Weitian; Yi, Hongliang; Li, Dongmei; Xia, Ming; Fu, Jianzhong; Wu, Ning; Haan, Judy B. de; Shen, Nan; Zhang, Wenhong; Liu, Zheng; Yu, Di

doi:10.1038/s41590-021-00996-0

Cited by 231 publications

(134 citation statements)

References 51 publications

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“…A direct association of Se status with immune response after vaccinations has been suggested [ 30 ]. A recent study described how the Se-GPx4-ferroptosis pathway regulates function of follicular T-helper cells supporting antibody production [ 31 ]. Supplementation of Se was shown to increase GPx4 expression and antibody titres following Influenza vaccination [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Humoral immune response to COVID-19 mRNA vaccination in relation to selenium status

et al. 2022

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The essential trace element selenium (Se) is of central importance for human health and particularly for a regular functioning of the immune system. In the context of the current pandemic, Se deficiency in patients with COVID-19 correlated with disease severity and mortality risk. Selenium has been reported to be associated with the immune response following vaccination, but it is unknown whether this also applies to SARS-CoV-2 vaccines. In this observational study, adult health care workers (n = 126) who received two consecutive anti-SARS-CoV-2 vaccinations by BNT162b2 were followed for up to 24 weeks, with blood samples collected at the first and second dose and at three and 21 weeks after the second dose. Serum SARS-CoV-2 IgG titres, neutralising antibody potency, total Se and selenoprotein P concentrations, and glutathione peroxidase 3 activity were quantified. All three biomarkers of Se status were significantly correlated at all the time points, and participants who reported supplemental Se intake displayed higher Se concentrations. SARS-CoV-2 IgG titres and neutralising potency were highest three weeks after the second dose and decreased towards the last sampling point. The humoral immune response was not related to any of the three Se status biomarkers. Supplemental Se intake had no effect at any time point on the vaccination response as measured by serum SARS-CoV-2 IgG levels or neutralising potency. Overall, no association was found between Se status or supplemental Se intake and humoral immune response to COVID-19 mRNA vaccination.

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Section: Introductionmentioning

confidence: 99%

Humoral immune response to COVID-19 mRNA vaccination in relation to selenium status

et al. 2022

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“…Neutrophils from systemic lupus erythematosus (SLE) patients exhibit ferroptosis due to the transcriptional repression of GPX4 [30]. In adaptive immunity, GPX4 is essential for maintaining the metastasis of TFH cells, and promotes humoral immune responses [31]. Ferroptosis of non-leukocytic cells often results in the release and activation of a different damage-associated molecular pattern (DAMP), triggering the inflammatory responses [32,33].…”

Section: Introductionmentioning

confidence: 99%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.

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“…LONP1 has also been reported to be involved in ferroptosis by regulating GPX4 ( Wang et al, 2020a ). It has been previously reported that ferroptosis is involved in regulating CD4 + T cell homeostasis ( Yao et al, 2021 ). Our results further revealed that the hub FRGs mainly regulate the T cell receptor signaling pathway, NIK/NF-kappaB signaling pathway, and Wnt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The study of CD4 + T cells has tremendous potential to contribute to cancer immunotherapy ( Yuan et al, 2017 ). It has been previously reported that ferroptosis is involved in regulating CD4 + T cell homeostasis, which enhances the function of follicular helper T cells during infection and following vaccination ( Yao et al, 2021 ). However, the function of ferroptosis in the regulation of the GC microenvironment and the upstream regulators of ferroptosis-related genes (FRGs) are worth further exploration.…”

Section: Introductionmentioning

confidence: 99%

LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

Yao

et al. 2021

Front. Cell Dev. Biol.

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Gastric cancer (GC) is a malignant disease of the digestive tract and a life-threatening disease worldwide. Ferroptosis, an iron-dependent cell death caused by lipid peroxidation, is reported to be highly correlated with gastric tumorigenesis and immune cell activity. However, the underlying relationship between ferroptosis and the tumor microenvironment in GC and potential intervention strategies have not been unveiled. In this study, we profiled the transcriptome and prognosis data of ferroptosis-related genes (FRGs) in GC samples of the TCGA-STAD dataset. The infiltrating immune cells in GC were estimated using the CIBERSORT and XCELL algorithms. We found that the high expression of the hub FRGs (MYB, PSAT1, TP53, and LONP1) was positively correlated with poor overall survival in GC patients. The results were validated in an external GC cohort (GSE62254). Further immune cell infiltration analysis revealed that CD4+ T cells were the major infiltrated cells in the tumor microenvironment of GC. Moreover, the hub FRGs were significantly positively correlated with activated CD4+ T cell infiltration, especially Th cells. The gene features in the high-FRG score group were enriched in cell division, DNA repair, protein folding, T cell receptor, Wnt and NIK/NF-kappaB signaling pathways, indicating that the hub FRGs may mediate CD4+ T cell activation by these pathways. In addition, an upstream transcriptional regulation network of the hub FRGs by lncRNAs was also developed. Three lncRNAs (A2M-AS1, C2orf27A, and ZNF667-AS1) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA A2M-AS1, C2orf27A, and ZNF667-AS1 may target the hub FRGs and impair CD4+ T cell activation, which finally leads to poor prognosis of GC. Effective interventions for the above lncRNAs and the hub FRGs can help promote CD4+ T cell activation in GC patients and improve the efficacy of immunotherapy. These findings provide a novel idea of GC immunotherapy and hold promise for future clinical application.

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Selenium–GPX4 axis protects follicular helper T cells from ferroptosis

Cited by 231 publications

References 51 publications

Humoral immune response to COVID-19 mRNA vaccination in relation to selenium status

Humoral immune response to COVID-19 mRNA vaccination in relation to selenium status

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

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