Plasmodium falciparum HRP2-induced damage to brain cortical organoids damage is Toll-Like Receptor dependent and is attenuated via Neuregulin-1/ErbB4 signaling
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PROVIDER: PRJNA788391 | ENA |
REPOSITORIES: ENA
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Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum (P.f.) infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB) and perivascular cellular injury. P.f. histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin 1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified Toll Like Receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.
2022-06-08 | GSE190750 | GEO
Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum infection associated with high mortality rates predominantly in children that live in sub-Saharan Africa. Histine rich protein 2 (HRP2) is a diagnostic and prognostic marker that can be detected in peripheral blood, cerebrospinal fluid and cord blood. Recent studies confirm that HRP2 crossess the compromised blood brain barrier (BBB) during HCM and infiltrate brain parenchyma. Treatments with HRP2 in murine experimental cerebral malaria (ECM) model recapitulate these effects. We tested the hypothesis that treatment of induced pluripotent stem cells (iPSC)-derived brain cortical organoids with HRP2 will recapitulate the brain effects. We assessed the effects of HRP2 treatment on ultrastructure, expression of markers of viability and inflammation neurons, astrocytes and microglia in organoids. We tested the neuroprotective effects of Neuregulin 1 (NRG1) against the HRP2 treatment. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.
2021-12-01 | GSE172366 | GEO
Project description:Plasmodium falciparum HRP2-mediated brain cortical organoid damage is Toll-Like Receptor dependent and is attenuated via Neuregulin-1/ErbB4 signaling
| PRJNA723032 | ENA
Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum (P.f.) infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB), perivascular cellular injury, and brain swelling. P.f.histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin-1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified toll-like receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous acute treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain.
| S-EPMC9157207 | biostudies-literature
Project description:The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co-expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells indicated that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies
2016-01-15 | PXD002665 | Pride
Project description:Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (Ecs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of ERBB4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC–specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (Ang II) or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC–specific Erbb4 knockout mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC–specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatio-temporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.
2020-05-15 | GSE150619 | GEO
Project description:Transcriptional profiling of ErbB4-/- mouse liver tissues comparing controls. Two-condition experiment, ErbB4-/- vs. control mouse liver tissues. Biological replicates: 3 controls, 3 ErbB4-/- mice.
2014-09-04 | E-GEOD-61056 | biostudies-arrayexpress
Project description:Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds.
2021-02-11 | GSE166524 | GEO
Project description:ERBB4 is a member of the epidermal growth factor receptor (EGFR)/ERBB subfamily of receptor tyrosine kinases that regulates cellular processes including proliferation, migration and survival. ERBB4 signaling is involved in embryogenesis and homeostasis of adult tissues, but also in human pathologies such as cancer, neurological disorders and cardiovascular diseases. A mass spectrometry screen revealed guanine nucleotide exchange factor (GEF) VAV3, an activator of Rho family GTPases, as a novel ERBB4-interacting protein in breast cancer cells. The ERBB4-VAV3-interaction was confirmed by targeted mass-spectrometry, coimmunoprecipitation experiments, and further defined by demonstrating that kinase activity and tyrosine residues 1022 and 1162 of ERBB4, as well as the intact phosphotyrosine-interacting SH2 domain of VAV3 were necessary for the interaction. ERBB4 was also shown to stimulate tyrosine phosphorylation of the VAV3 activation domain, which is required for GEF activity of VAV proteins. In addition to VAV3, also the other members of the VAV family, VAV1 and VAV2 were shown to coprecipitate with ERBB4. Analyses of the effects of overexpression of dominant-negative VAV3 constructs or downregulation of VAV3 expression by shRNAs in breast cancer cells demonstrated that active VAV3 was involved in ERBB4-stimulated migration. These findings define the VAV GTPases as novel effectors of ERBB4 activity in a signaling pathway relevant for cancer cell migration.
2020-06-24 | PXD019430 | Pride
Project description:Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that HRP2-DPF3a-BAF complex coordinates histone H3 lysine 36 methylation (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamic and gene transcription during myogenic differentiation. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with BRG1/BRM associated factor (BAF) chromatin remodeling complex by direct interaction with BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, genome-wide analyses show that HRP2 colocalizes with DPF3a at gene promoters enriched for H3K36me2.
2020-05-13 | GSE148295 | GEO