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:Objective Increased neutrophil extracellular trap-osis (NETosis) is a hallmark of inflammatory bowel disease (IBD). However, the mechanisms of NETosis formation and its detrimental effect on the intestinal epithelium remain poorly understood. Design Dextran sulfate sodium (DSS) induce colitis in peptidyl-arginine deiminase-4 deficient (PAD4-/-) and wild-type (WT) mice. PAD4, NETosis and citrullination levels were detected in mice and human volunteers. Citrullination analysis and single-cell RNA-sequencing (scRNA-seq) were performed to explore the target of PAD4 during NETosis formation. The effect of this citrullinated target in the intestinal epithelium during the pathogenesis of IBD was validated both in vivo and in vitro. Results The levels of NETosis and citrullination were improved in IBD patients, which was positively associated with endoscopic inflammation scores. Deleting PAD4 alleviated colonic inflammation and intestinal barrier dysfunctions. In citrullination analysis, R243 of mitochondrial creatine kinase 1 (CKMT1) was identified as the potential target of PAD4 during NETosis. The scRNA-seq data further indicated that PAD4 in neutrophils contributed to the increase of epithelia (Nos2+ Clca3b+) and the decrease of distal immature epithelia. PAD4-mediated NETosis contributed to the destruction of intestinal barriers and increase of apoptosis as well as lower level of CKMT1 protein in vitro. Finally, mice with intestinal epithelial-specific ablation of CKMT1 were used to verify its detrimental role in the development of IBD, which was also validated by the moderate correlation between CKMT1 and endoscopic scores in IBD patients.
2025-06-09 | PXD041504 | Pride
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.
2023-12-27 | GSE241485 | 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: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:Myocarditis is an inflammatory injury to the myocardium characterized by disrupted intercellular communication, involving macrophages and cardiomyocytes as key players. However, the interactions between macrophages and cardiomyocytes during myocarditis remain inadequately explored. Emerging evidence indicated that extracellular vesicles (EVs) play a crucial role in intercellular communication. Here, we demonstrated that large EVs derived from lipopolysaccharide (LPS)-preconditioned cardiomyocytes (C-lEVLPS) exhibited anti-inflammatory effects on macrophages and alleviated cardiac inflammation and dysfunction in a mouse model of CVB3-induced myocarditis. Additionally, C-lEVLPS facilitated macrophage polarization toward the M2-like phenotype and inhibits M1 polarization, both in vitro and in vivo. label-free proteomics analysis showed, compared to phosphate-buffered saline (PBS)-preconditioned cardiomyocytes (C-lEVPBS), C-lEVLPS was enriched in the phosphatase 2 scaffold subunit alpha protein (PP2AA), which can recruit other subunits to form the PP2A complex, ultimately leading to the dephosphorylates of p38. This study highlights the effect of C-lEVLPS in myocarditis and uncovers the potential mechanism that modulates macrophage polarization by delivering PP2AA from cardiomyocytes to macrophages and regulating the p38 MAPK pathway. These findings provide a promising therapeutic strategy for myocarditis.
2025-09-29 | PXD057460 | Pride
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.
2021-05-05 | GSE173807 | GEO
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:Peptidyl Arginine Deiminase 4 (PAD4) is an enzyme predominantly expressed in myeloid cells, and its role in diabetic kidney disease (DKD) remains unknown. We functionally characterized 48 PAD4 variants identified among 469,779 participants from UK Biobank and examined their associations with renal function. We found that 32 PAD4 variants causes loss of function, which was significantly associated with higher estimated glomerular filtration rate. We observed an enhanced PAD4 expression in renal tubulointerstitium among DKD patients and animal models of DKD. Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD.
2025-10-16 | GSE279745 | GEO