N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner

Shen, Hao; Xie, Keliang; Li, Miaomiao; Yang, Qianyu; Wang, Xiaoye

doi:10.1038/s41420-022-01099-x

Cited by 31 publications

(17 citation statements)

References 32 publications

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“…In recent years, it has been gradually recognised that ferroptosis correlates with the occurrence and progression of various diseases, including ALI 21 . m6A modification has recently attracted attention because of its vital role in gene expression regulation 22–25 . In our previous study, we identified that m6A levels are significantly upregulated in NET‐treated alveolar epithelial cells in vitro and by modulating METTL3 expression through knockdown or overexpression in alveolar epithelial cells, we demonstrated that METTL3 is a crucial contributor to m6A levels 16,26 .…”

Section: Introductionmentioning

confidence: 67%

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Zhang,

Wu,

Wang

et al. 2023

Clinical & Translational Med

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Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis‐induced acute lung injury (SI‐ALI). We demonstrate that NETs induce SI‐ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI‐ALI is accompanied by upregulation of ferroptosis depending on METTL3‐induced m6A modification of hypoxia‐inducible factor‐1α (HIF‐1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI‐ALI caused by NETs in a caecum ligation and puncture (CLP)‐induced SI‐ALI model using METTL3 condition knockout (CKO) mice and wild‐type mice. Our results indicate the crucial role of NETs in the progression of SI‐ALI via NET‐activated METTL3 m6A‐IGF2BP2‐dependent m6A modification of HIF‐1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.

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Section: Introductionmentioning

confidence: 67%

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Zhang,

Wu,

Wang

et al. 2023

Clinical & Translational Med

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“…The pathophysiological mechanism of sepsis-induced myocardial injury is complex, involving both pathogens and the host immune system. It has also been demonstrated that m 6 A methylation plays a significant regulatory role in sepsis-induced myocardial injury ( 24 ). Shen et al.…”

Section: Resultsmentioning

confidence: 99%

An overview of the effects and mechanisms of m6 A methylation on innate immune cells in sepsis

Qian

Cao

2022

Front. Immunol.

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IntroductionSepsis is a severe clinical syndrome caused by dysregulated systemic inflammatory responses to infection. Methylation modification, as a crucial mechanism of RNA functional modification, can manipulate the immunophenotype and functional activity of immune cells to participate in sepsis progression. This study aims to explore the mechanism of N6-methyladenosine (m6A) methylation modification in immune cell-mediated sepsis through keyword search.MethodsLiterature retrieval.Results and DiscussionLiterature retrieval reveals that m6A methylation is implicated in sepsis-induced lung injury and myocardial injury,as well as sepsis-related encephalopathy. Furthermore, it is found that m6A methylation can regulate sepsis by inhibiting the chemotaxis of neutrophils and the formation of neutrophil extracellular traps and suppressing macrophage phagocytosis, thereby playing a role in sepsis.

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“…Apart from the roles in neoplastic diseases, IGF2BP1 is also involved in several nonneoplastic conditions. For example, the role of the METTL3/IGF2BP1/HDAC4 axis was illustrated in sepsis-associated myocardial injury, providing a novel therapeutic strategy 73 . In this study, we found high IGF2BP1 expression in septic AKI and that the level of IGF2BP1 was positively correlated with pyroptosis in renal tubular cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway

Mao

Jiang

et al. 2023

Int. J. Biol. Sci.

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Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and is associated with the development of septic AKI. This study found that induction of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory factor (MIF), a subunit of NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site was identified at the 3′-UTR region of E2F transcription factor 1 (E2F1) mRNA via bioinformatics analyses and validated using mutation and luciferase experiments. Further actinomycin D (Act D) chase experiments showed that IGF2BP1 stabilized E2F1 mRNA dependent on m6A. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) indicated that E2F1 acted as a transcription factor to promote MIF expression. Thus, IGF2BP1 upregulated MIF through directly upregulating E2F1 expression via m6A modification. Experiments on mice with cecum ligation puncture (CLP) surgery verified the relationships between IGF2BP1, E2F1, and MIF and demonstrated the significance of IGF2BP1 in MIF-associated pyroptosis in vivo. In conclusion, IGF2BP1 was a potent pyroptosis inducer in septic AKI through targeting the MIF component of NLRP3 inflammasomes. Inhibiting IGF2BP1 could be an alternate pyroptosis-based treatment for septic AKI.

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N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner

Cited by 31 publications

References 32 publications

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

An overview of the effects and mechanisms of m6 A methylation on innate immune cells in sepsis

Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway

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