Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1039573 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26800677_1.fastq.gz | Fastqsanger.gz | |||
| SRR26800677_2.fastq.gz | Fastqsanger.gz | |||
| SRR26800678_1.fastq.gz | Fastqsanger.gz | |||
| SRR26800678_2.fastq.gz | Fastqsanger.gz | |||
| SRR26800679_1.fastq.gz | Fastqsanger.gz |
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Project description:Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival
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Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
2025-05-07 | PXD057003 | Pride
Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
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Project description:Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling have been reported to be causal in cytokine storm associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. We report using Usp18-deficient, USP18 enzymatic inactive and Isg15-deficient mouse models that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. Transcriptional studies of immune cells from mice bearing the enzymatic inactive version of USP18 (Usp18C61A) revealed a neutrophil influx in the lung of these animals during infection, associated with increased immature neutrophil content. These neutrophil differentiation changes were dependent on ISG15 as deletion of Isg15 from C61A animals reversed the accumulation of immature neutrophils. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18C61A mice. In summary, we reveal Usp18 enzymatic function is crucial for regulating extracellular release of ISG15 which are accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection.
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Project description:COVID-19 has posed a significant threat to global health. Early data has revealed that IL-6, a key regulatory cytokine, plays an important role in the cytokine storm of COVID-19. Multiple trials are therefore looking at the effects of Tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity, on treatment of COVID-19, with promising findings. As part of a clinical trial looking at the effects of Tocilizumab treatment on kidney transplant recipients with subclinical rejection, we performed single-cell RNA sequencing of comparing stimulated PBMCs before and after Tocilizumab treatment. We leveraged this data to create an in vitro cytokine storm model, to better understand the effects of Tocilizumab in the presence of inflammation. Tocilizumab-treated cells had reduced expression of inflammatory-mediated genes and biologic pathways, particularly amongst monocytes. These results support the hypothesis that Tocilizumab may hinder the cytokine storm of COVID-19, through a demonstration of biologic impact at the single-cell level.
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Project description:sn-RNAseq profiling of the impact of a cytokine storm model in human cardiac organoids
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Project description:Lethal Cytokine Storm Post-mRNA Booster Vaccination
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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.
2020-12-03 | GSE160163 | GEO
Project description:Adult hematopoietic stem cells (HSCs) respond directly to inflammation and infection, resulting in both acute and persistent changes in quiescence, mobilization, and differentiation. Here we show that fetal HSCs respond to maternal inflammation in utero, and the fetal response drives long-term changes to postnatal hematopoiesis and immunity. Heterogeneous fetal hematopoietic stem and progenitor cells (HSPCs) show divergent responses to maternal immune activation (MIA), including changes in quiescence, expansion, and immune cell output. Single cell transcriptomic analysis of fetal HSPCs reveals specific upregulation of inflammation-responsive genes in discrete populations, in response to upregulated IFNα and IL-1α in the fetal liver cytokine milieu. Postnatally, MIA caused the inappropriate expansion and persistence of transient progenitors, concomitant with increased cellularity and hyper-responsiveness of fetal-derived immune cells. Our investigation demonstrates how inflammation in utero can direct the trajectory of hematopoiesis and immunity by reshaping fetal HSC establishment.
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