Extracellular Vesicles Derived from Inflammatory Cardiomyocytes Mediate Macrophage Polarization and Alleviate Myocarditis via p38 MAPK Pathway
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279575 | GEO | 2024/10/23
REPOSITORIES: GEO
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Project description:Extracellular Vesicles Derived from Inflammatory Cardiomyocytes Mediate Macrophage Polarization and Alleviate Myocarditis via p38 MAPK Pathway
| PRJNA1173537 | ENA
Project description:Acute liver failure is a clinical syndrome of severe hepatic dysfunction. Immune cells play an important role in the failure. In recent years, the immunoregulatory function of extracellular vesicles (EVs) has been reported; therefore, it is inferred that EVs have some role in an immune mediated liver injury. In this study, we investigated the immunoregulatory function of EVs in a concanavalin A (Con A)-induced liver injury. The mouse model was prepared by a single intravenous administration of 15 mg/kg Con A, in which there was a significant increase in serum EVs number. In in vitro study, the secreted EVs number was also significantly increased in Con A-treated RAW264.7, a mouse macrophage cell line, but not Hepa1-6, a mouse hepatoma cell line. In in vitro EVs treatment study, the EVs from Con A-treated mice serum and Con A-treated RAW264.7 suppressed the inflammatory cytokines production in Con A-stimulated RAW264.7. miRNA sequencing analysis showed that mmu-miR-122-5p and mmu-miR-148a-3p were commonly increased in these EVs and the EVs-treated cells. The enriched pathways in the miRNAs predicted target genes included the inflammatory response pathways. mRNA levels of the target genes in the pathways (mitogen-activated protein kinase, Phosphoinositide 3-kinase/Akt and Rho/Rho associated coiled-coil containing protein kinase pathways) were decreased in the EVs-treated cells. In in vivo RNA interference study, knock down of liver RAB27A, an EVs secretion regulator, significantly exacerbated the Con A-induced liver injury. These data suggest that macrophage-derived EVs play an important role in a Con A-induced liver injury through the immunoregulation.
2020-03-20 | GSE147243 | GEO
Project description:Macrophages are key immune cells in inflammatory bowel disease (IBD) that can exhibit different phenotypes and promote inflammation. Alcohol consumption is associated with increased risk and severity of IBD. We performed in vitro and in vivo experiments with dextran sodium sulfate-induced mice colitis model, peritoneal macrophages and RAW264.7 cell line to investigate the effect and mechanism of alcohol on macrophages in colitis. Our study has found that alcohol exacerbates colitis in mice, increases the aggregation of colonic macrophages, and promotes the production of various inflammatory factors. Alcohol increases lipopolysaccharides (LPS)-induced calcium influx in macrophages, which is inhibited by the TRPV1 antagonist Capsazepine (CPZ). Alcohol and LPS together induce M2b polarization of macrophages and promote the phosphorylation and nuclear translocation of P38, ERK1/2 and NF-κB, and could be inhibited by CPZ and NOD2 inhibitor. Thus, alcohol can aggravate experimental colitis in mice and promote macrophage M2b polarization through the TRPV1-MAPK/NF-kB pathways.
2023-07-24 | GSE237785 | GEO
Project description:As mediators of intercellular communication, exosomes containing molecular cargo are secreted by cells and taken up by recipient cells to influence cellular phenotype and function. Here we have investigated the effects of exosomes in dystrophin-deficient (Dys) induced pluripotent stem cell derived cardiomyocytes (iCMs). Our data demonstrate that exosomes secreted from either wild type (WT) or Dys-iCMs protect the Dys-iCM from stress-induced injury by decreasing reactive oxygen species and delaying mitochondrial permeability transition pore opening to maintain the mitochondrial membrane potential and decrease cell death. The protective effects of exosomes were dependent on the presence of exosomal surface proteins and activation of ERK1/2 and p38 MAPK signaling. Based on our findings, the acute effects of exosomes on recipient cells can be initiated from exosome membrane proteins and not necessarily their internal cargo.
| S-EPMC6224575 | biostudies-literature
Project description:Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.
| S-EPMC4754716 | biostudies-literature
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38M-NM-1 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38M-NM-1 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS WT vs. p38alphaCKO macrophages, male vs. female
2013-10-29 | E-GEOD-51707 | biostudies-arrayexpress
Project description:P38MAPK mediates cytokine induced inflammation in nucleus pulposus (NP) cells and involves in multiple cellular processes which are related to intervertebral disc degeneration (IDD). The aim of this study was to investigate the expression, activation and function of p38 MAPK isoforms (?,?, ? and ?) in degenerative NP and the effect of p38 activation in NP cells on macrophage polarization. P38 ?, ? and ? isoforms are preferential expressed, whereas the p38? isoform is absent in human NP tissue. LV-sh-p38?, sh-p38? transfection in NP cells significantly decreased the ADAMTS-4,-5, MMP-13,CCL3 expression and restored collagen-II and aggrecan expression upon IL-1? stimulation. As compared with p38? and p38?, p38? exhibited an opposite effect on ADAMTS-4,-5, MMP-13 and aggrecan expression in NP cells. Furthermore, the production of GM-CSF and IFN? which were trigged by p38? or p38? in NP cells induced macrophage polarization into M1 phenotype. Our finding indicates that p38 MAPK ?, ? and ? isoform are predominantly expressed and activated in IDD. P38 positive NP cells modulate macrophage polarization through the production of GM-CSF and IFN?. Hence, Our study suggests that selectively targeting p38 isoforms could ameliorate the inflammation in IDD and regard IDD progression.
| S-EPMC4766431 | biostudies-literature
Project description:This study was aimed at identifying molecular markers associated with the pathogenesis of sudden cardiac death (SCD). It provides a proteomic analysis of human left anterior descending coronary artery from subjects diagnosed with SCD through histological examination and cases of nondisease accidental deaths through autopsy. A total of 2784 proteins were obtained from label-free quantitative proteomic analysis. This included a total of 265 differential proteins which were involved in SCD-related processes, such as inflammation, muscle system process regulation, metal ion transport, and lysosomal pathway. Western blotting was carried out to measure the expressions of cathepsin C (CTSC), focal adhesion kinase (FAK), p-FAK, and proteins related to the p38/MAPK signaling pathway, whereas immunohistochemistry was performed to determine the localization and expression of CTSC, TNF-α, and CD206 in arterial tissues. It was found that CTSC were the most expressed proteins with a significant upward trend in SCD cases. Besides, CTSC regulated macrophage polarization to M1 through the FAK-induced p38/MAPK signaling pathway. This promoted the release of inflammatory factors and eventually increased the inflammatory response. In conclusion, this study implies that CTSC may be one of the key molecular targets for promoting macrophage M1 polarization in SCD, which may provide new therapeutic insights into the treatment of inflammatory diseases.
| S-EPMC8536465 | biostudies-literature
Project description:BackgroundOur previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF)-1? during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1? caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL), as a ubiquitin ligase, is best understood as a negative regulator of HIF-1?.Methodology/principal findingsIn primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4) overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1? were down-regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu) overexpression increased pVHL in the microtubule network altered-hypoxic cardiomyocytes and H9c2 cells.Conclusions/significanceThis study suggests that pVHL plays an important role in the regulation of HIF-1? caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes.
| S-EPMC3323643 | biostudies-literature
Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Keywords: Gene transfer
2006-12-19 | GSE3866 | GEO