Inhibition of NETosis via PAD4 could alleviate the inflammation of giant cell myocarditis
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ABSTRACT:
PROVIDER: PRJNA912772 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22758226_1.fastq.gz | Fastqsanger.gz | |||
| SRR22758226_2.fastq.gz | Fastqsanger.gz | |||
| SRR22758227_1.fastq.gz | Fastqsanger.gz | |||
| SRR22758227_2.fastq.gz | Fastqsanger.gz |
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Project description:Giant cell myocarditis (GCM) is a rare, often rapidly progressive and potentially fatal, disease caused by T-cell-mediated cardiac inflammation that typically affects young and middle-aged adults. The detailed inflammatory response remained unknown, especially the formation of multinucleate giant cells.Methods and Results: Rats were treated with myosin heavy-chain-α peptides to generate a GCM model. We performed single-cell RNA sequencing analysis of 15,714 Cd45 + cells extracted from hearts from GCM rat model and normal rats. We identified 24 subclusters including macrophages, neutrophils, T cells and so on. The GCM was characteristic with macrophage cluster 1, neutrophil cluster 3, macrophage cluster 2, neutrophil cluster 1 and Th17 cells. Two specific macrophage clusters involved in the GCM have roles in phagocytosis, and NETosis was found to contribute into the process of GCM. Its receptor, Ccdc25 , expressed in the macrophage cluster 1 and Th17, suggesting that neutrophils could regulate other immune cells in GCM. Importantly, inhibitor of NETosis, GSK484, could alleviate the inflammation of GCM in vivo. Finally, MPO (a marker of neutrophils) and H3cit (a marker of NETosis) were expressed at higher levels in GCM patients than in DCM patients and healthy controls and neutrophils were part of multinucleated giant cells. IMC analysis revealed that the formation of multinucleate giant cells of GCM.Conclusions: We herein present a comprehensive single-cell landscape of the cardiac immune cells in GCM. In addition, we elucidated the contribution of NETosis to the pathogenesis of GCM, which may serve as a potential therapeutic target in the clinic.
2023-06-15 | GSE221111 | GEO
Project description:Giant cell myocarditis (GCM) is a rare, usually rapidly progressive, and potentially fatal disease. Detailed inflammatory responses remain unknown, in particular the formation of multinucleate giant cells. We performed single-cell RNA sequencing analysis on 15,714 Cd45+ cells extracted from the hearts of GCM rats and normal rats. NETosis has been found to contribute to the GCM process. An inhibitor of NETosis, GSK484, alleviated GCM inflammation in vivo. MPO (a marker of neutrophils) and H3cit (a marker of NETosis) were expressed at higher levels in patients with GCM than in patients with DCM and healthy controls. Imaging mass cytometry analysis revealed that immune cell types within multinucleate giant cells included CD4+ T cells, CD8+ T cells, neutrophils, and macrophages but not B cells. We elucidated the role of NETosis in GCM pathogenesis, which may serve as a potential therapeutic target in the clinic.
| S-EPMC10391931 | biostudies-literature
Project description:Neutrophil extracellular traps (NETs) counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptormediated apoptosis promote GSDME-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils, and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils, but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end-of-life for neutrophils.
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Project description:This experiment was designed to identify transcripts which are changed in plants deficient for evolutionary conserved EST1B gene. A mutation in est1b leads to a constitutive up-regulation of a PAD4-dependent pathogen response pathway. To eliminate secondary effects of the constitutive pathogen response in est1b mutants we will analyze transcriptoms in plants in which lack PAD4. Keywords: Expression profilling by array
2009-11-18 | GSE18979 | GEO
Project description:This experiment was designed to identify transcripts which are changed in plants deficient for evolutionary conserved EST1B gene. A mutation in est1b leads to a constitutive up-regulation of a PAD4-dependent pathogen response pathway. To eliminate secondary effects of the constitutive pathogen response in est1b mutants we will analyze transcriptoms in plants in which lack PAD4. Keywords: Expression profilling by array 6 samples were used in this experiment
2009-11-17 | E-GEOD-18979 | biostudies-arrayexpress
Project description:TcpC is a multifunctional virulence factor of uropathogenic E. coli (UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. In situ NETosis of kidneys from pyelonephritis mouse model induced by TcpC-secreting wild-type CFT073 (CFT073wt) and LPS-induced in vitro NETosis in CFT073wt- or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses suggest that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.
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Project description:Extracellular Vesicles Derived from Inflammatory Cardiomyocytes Mediate Macrophage Polarization and Alleviate Myocarditis via p38 MAPK Pathway
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Project description:We found PAD4, which is one of the transcriptional co-regulator by histone modification, was highly expressed in lineage-, Sca-1+, c-kit+ (termed as LSK) cells of mouse bone marrow. To find the target genes which are regulated by PAD4 in LSK cells, we analyzed gene expression in PAD4-deficient mouse as compared with wild-type mouse. Gene expression in wild-type and PAD4-deficient LSK cells
2013-06-01 | E-GEOD-45482 | biostudies-arrayexpress
Project description:We found PAD4, which is one of the transcriptional co-regulator by histone modification, was highly expressed in lineage-, Sca-1+, c-kit+ (termed as LSK) cells of mouse bone marrow. To find the target genes which are regulated by PAD4 in LSK cells, we analyzed gene expression in PAD4-deficient mouse as compared with wild-type mouse.
2013-06-01 | GSE45482 | GEO
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