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

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(9)

Опубликована: Сен. 1, 2023

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 Although lung is highly vulnerable infections, few studies have explored role sepsis-induced acute injury (SI-ALI). We demonstrate that induce SI-ALI via enhanced ferroptosis alveolar epithelial cells. Our findings reveal excessive release patients mice with accompanied upregulation depending on METTL3-induced m6A modification hypoxia-inducible factor-1α (HIF-1α) subsequent mitochondrial metabolic reprogramming. In addition conducting METTL3 overexpression knockdown experiments vitro, we investigated impact caused caecum ligation puncture (CLP)-induced model using condition knockout (CKO) wild-type mice. results indicate crucial progression NET-activated m6A-IGF2BP2-dependent HIF-1α, which further contributes reprogramming

Язык: Английский

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S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

Cell Death and Disease, Год журнала: 2024, Номер 15(6)

Опубликована: Июнь 28, 2024

Abstract S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in variety inflammatory diseases. Although S100a8/a9 has been reported trigger endothelial cell apoptosis, mechanisms S100a8/a9-induced dysfunction during sepsis require in-depth research. We demonstrate that high expression levels suppress Ndufa3 mitochondrial complex I via downregulation Nrf1 expression. Mitochondrial deficiency contributes NAD + -dependent Sirt1 suppression, which induces disorders, including excessive fission blocked mitophagy, mtDNA from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis cells. Moreover, based on comprehensive scRNA-seq bulk RNA-seq analyses, S100A8/A9 hi are closely associated with circulating count (a useful marker damage), S100A8 is an independent risk factor for poor prognosis patients.

Язык: Английский

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Neutrophil extracellular traps in central nervous system pathologies: A mini review

Frontiers in Medicine, Год журнала: 2023, Номер 10

Опубликована: Фев. 17, 2023

Neutrophils are the first cells to be recruited sites of acute inflammation and contribute host defense through phagocytosis, degranulation neutrophil extracellular traps (NETs). rarely found in brain because highly selective blood-brain barrier (BBB). However, several diseases disrupt BBB cause neuroinflammation. In this regard, neutrophils NETs have been visualized after various insults, including traumatic (traumatic injury spinal cord injury), infectious (bacterial meningitis), vascular (ischemic stroke), autoimmune (systemic lupus erythematosus), neurodegenerative (multiple sclerosis Alzheimer’s disease), neoplastic (glioma) causes. Significantly, preventing trafficking into central nervous system or NET production these alleviates pathology improves neurocognitive outcomes. This review summarizes major studies on contribution (CNS) disorders.

Язык: Английский

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Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 5034 - 5034

Опубликована: Март 6, 2023

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) released into space to defend against invading pathogens. Although NETs play a defensive role pathogens, excessive can contribute pathogenesis airway diseases. known be directly cytotoxic lung epithelium endothelium, highly involved in acute injury, implicated disease severity exacerbation. This review describes NET formation diseases, including chronic rhinosinusitis, suggests targeting could therapeutic strategy for

Язык: Английский

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Emerging role of METTL3 in inflammatory diseases: mechanisms and therapeutic applications

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Авг. 21, 2023

Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney and autoimmune diseases have high incidence rates, still threaten human health, represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis various diseases. As most widely discussed m6A methyltransferase, pathogenic role METTL3 has become research hotspot, but there been no comprehensive review topic. Here, we summarize expression changes, modified target genes, related cardiovascular, metabolic, degenerative, immune, infectious well tumors. In addition epithelial cells, endothelial fibroblasts, also regulates function inflammation-related immune including macrophages, neutrophils, dendritic Th17 NK cells. Regarding therapeutic applications, serves for treatment with natural plant drug components, emodin, cinnamaldehyde, total flavonoids Abelmoschus manihot , resveratrol. This focuses on recent advances initiation, development, application Knowledge specific regulatory mechanisms involving can help deepen understanding lay foundation development precisely targeted drugs address processes.

Язык: Английский

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Neutrophil extracellular traps contribute to immunothrombosis formation via the STING pathway in sepsis-associated lung injury

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Авг. 25, 2023

Neutrophil extracellular traps (NETs) are involved in the activation and dysfunction of multiple overlapping interacting pathways, including immune response to injury, inflammation, coagulation, which contribute pathogenesis sepsis-induced acute lung injury (SI-ALI). However, how NETs mediate relationship between inflammation coagulation has not been fully clarified. Here, we found that NETs, through stimulator interferon genes (STING) activation, induced endothelial cell damage with abundant production tissue factor (TF), magnified dysregulation inflammatory coagulant responses resulted poor prognosis SI-ALI model mice. Disruption inhibition STING improved outcomes septic mice reduced coagulation. Furthermore, Toll-like receptor 2 (TLR2) on surface cells was interaction pathway. Collectively, these findings demonstrate activate cascade a STING-dependent manner development SI-ALI.

Язык: Английский

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METTL14 contributes to acute lung injury by stabilizing NLRP3 expression in an IGF2BP2-dependent manner

Cell Death and Disease, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 13, 2024

Abstract Acute lung injury (ALI) as well its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N 6 -methyladenosine (m A) modification was associated with the progression of several diseases. However, role methyltransferase-like 14 (METTL14)-mediated m A methylation in ALI/ARDS remains unclear. Here, we reported increase overall expression levels and METTL14 circulating monocyte-derived macrophages recruited following ALI, which is correlated severity injury. We further demonstrated critical function activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome vitro mouse models ALI/ARDS, validated NLRP3 downstream target by RNA immunoprecipitation (MeRIP) RIP assays. Mechanistically, METTL14-methylated transcripts were subsequently recognized insulin-like growth factor 2 mRNA-binding (IGF2BP2), reader, stabilized mRNA. Furthermore, observed that IGF2BP2 knockdown diminished LPS-induced ALI mice downregulating expression. In summation, our study revealed molecular mechanism underlying pathogenesis involves METTL14-mediated activation dependent manner, thereby demonstrating potential promising biomarkers therapeutic targets for treatment.

Язык: Английский

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SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury

International Journal of Surgery, Год журнала: 2024, Номер unknown

Опубликована: Март 4, 2024

Background: Acute lung injury (ALI) is a leading cause of mortality in patients with sepsis due to proinflammatory endothelial changes and permeability defects. Mitochondrial dysfunction recognized as critical mediator the pathogenesis sepsis-induced ALI. Although mitophagy regulation mitochondrial quality well recognized, little known about its role ECs during Sirtuin 1 (SIRT1) histone protein deacetylase involved inflammation, mitophagy, cellular senescence. Here, authors show type late endosome-dependent that inhibits NLRP3 STING activation through SIRT1 signaling Methods: C57BL/6J male mice or without administration inhibitor EX527 CLP model vitro were developed identify mechanisms underlie cross-talk between Results: deficient exhibited exacerbated Knockdown interfered endosome Rab7, accumulation damaged mitochondria inducing excessive reactive oxygen species (mtROS) generation cytosolic release DNA (mtDNA), which triggered inflammasome nucleotide sensing pathways (STING) over-activation. Pharmacological inhibition i n vivo genetic knockdown reversed deficiency mediated defects inflammation Moreover, SRT1720 overexpression protected against Conclusion: These findings suggest essential for restricting hyperactivation by promoting endosomal-mediated ECs, providing potential therapeutic targets treating

Язык: Английский

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Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Фев. 2, 2024

Abstract Background Sepsis is a severe systemic inflammatory disorder manifested by dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis are able suggest patients’ prognoses. At the same time, specific mechanism of ferritin-induced injury remains unclear. Methods Hyper-ferritin state inflammation was performed injecting into mouse model demonstrated injection could induce increase neutrophil extracellular trap (NET) formation.Padi4 −/− , Elane Cybb mice were used for NETs formation experiment. Western blot, immunofluorescence, ELISA, flow cytometry examined changes in NETs, inflammation, related signaling pathways. Results Ferritin induces NET peptidylarginine deiminase 4 (PAD4), elastase (NE), reactive oxygen species (ROS)-dependent manner, thereby exacerbating response. Mechanistically, expression macrophage scavenger receptor (MSR), which promotes NETs. Clinically, high patients with correlate NETs-mediated cytokines storm proportional severity sepsis-induced lung injury. Conclusions In conclusion, we hyper-ferritin can MSR-dependent manner. This process relies on PAD4, NE, ROS, further aggravating acute clinic, serum associated worse injury, suggests poor prognosis sepsis. Our study indicated targeting or MSR be potential treatment alleviate damage

Язык: Английский

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FTO Deficiency Alleviates LPS-induced Acute Lung Injury by TXNIP/NLRP3-mediated Alveolar Epithelial Cell Pyroptosis

American Journal of Respiratory Cell and Molecular Biology, Год журнала: 2024, Номер 70(5), С. 351 - 363

Опубликована: Янв. 25, 2024

N6-methyladenosine (m6A) plays a role in various diseases, but it has rarely been reported acute lung injury (ALI). The fat mass and obesity-associated (FTO) protein can regulate mRNA metabolism by removing m6A residues. This study aimed to examine the mechanism of demethylase FTO lipopolysaccharide (LPS)-induced ALI. Lung epithelial knockout mice knockdown/overexpression A549 cell lines were constructed evaluate effects on Bioinformatics analysis series vivo vitro assays used regulation. Rescue conducted whether impact ALI depended TXNIP/NLRP3 pathway. In LPS-induced ALI, RNA modification levels upregulated, expression was downregulated. vivo, alleviated alveolar structure disorder, tissue oedema, pulmonary inflammation improved survival mice. vitro, knockdown reduced damage death induced LPS, while overexpression exacerbated death. Mechanistically, bioinformatics revealed that TXNIP downstream target FTO. deficiency mitigated pyroptosis via confirmed pathway significantly reversed inhibitor SRI-37330. Deficiency alleviates pathway-mediated pyroptosis, which might be novel therapeutic strategy for combating

Язык: Английский

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