Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA600277 | ENA |
REPOSITORIES: ENA
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Project description:NF-kB is a transcriptional factor that consists in homo and heterodimers of the large family of Rel subunits. Among the most important functions for NF-kB, initiation of immunological/inflammatory responses and regulation of cell proliferation/apoptosis which are the major features of severe infections. Although the role of NF-kB is crucial in host defense against pathogens, mice deficient for individual subunits of NF-kB have not been explored in murine models of polymicrobial infection. In this report, we have investigated in vivo the consequences of cRel subunit deficiency in the survival to polymicrobial infection. We have also approached the underlying mechanisms of the host defense by analyzing cytokine production, bacterial clearance and the distribution of innate and adaptive immune cells. Absence of cRel enhances mice mortality to polymicrobial sepsis. The decreased survival of cRel-/- animals upon infection is not related to altered local mechanisms of innate defense such as the peritoneal recruitment of the Gr.1+CD11b+ phagocytic cells and the bacterial clearance. However, cRel deficiency allows to altered systemic cytokine response associated to sustained loss of the lymphoïd subset CD8a+ of spleen dendritic cells, key antigen-presenting cells for the initiation of the adaptive immunity. Genome-wide analysis of the systemic host response to polymicrobial sepsis reveals inflammatory/immune and apoptotic gene signatures associated to cRel subunit. In this study we identified the NF-kB member cRel, as a key factor which plays a critical role in survival to polymicrobial sepsis and also as a regulatory transcription subunit controlling the inflammatory and the adaptive immune responses in severe infection.
2011-10-14 | E-MEXP-2944 | biostudies-arrayexpress
Project description:Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)‒induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R‒HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns to address the lack of burn-specific treatments.
2023-12-18 | GSE241139 | GEO
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:Macrophage death in advanced atherosclerotic lesions is a key event in the conversion of benign lesions to vulnerable plaques. One fundamental transcription factor that has been shown to play a pivotal role in cell death/survival is nuclear factor kB (NF-kB). Still, the relevance of this key transcription factor for macrophage-derived foam cell survival has not been unequivocally resolved at the molecular level. THP-1 monocytic cell lines were generated in which NF-kB activation is specifically inhibited by overexpression of a trans-dominant, non-degradable form of IkBa (IkBa (32A/36A)) under control of the macrophage-specific SR-A promoter. A diminished lipid loading during NF-κB inhibition during foam cell formation was accompanied by increased cell death. A genome-wide expression profile of NF-kB-dependent genes during foam cell formation was established showing a widespread effect on the macrophage transcriptome. The three largest functional gene clusters identified and validated by independent techniques, were those involved in lipid metabolism, apoptosis and oxidative stress. The net result of these complex gene expression changes invoked by inhibition of NF-κB activation during lipid loading is a reduction of foam cell survival through caspase-dependent apoptosis. Thus, the NF-kB-dependent gene repertoire seems essential for sustained macrophage survival during the process of pathological lipid loading. Keywords: genetic modification, lipid loading, timecourse
2009-08-11 | GSE12434 | GEO
Project description:Macrophage death in advanced atherosclerotic lesions is a key event in the conversion of benign lesions to vulnerable plaques. One fundamental transcription factor that has been shown to play a pivotal role in cell death/survival is nuclear factor kB (NF-kB). Still, the relevance of this key transcription factor for macrophage-derived foam cell survival has not been unequivocally resolved at the molecular level. THP-1 monocytic cell lines were generated in which NF-kB activation is specifically inhibited by overexpression of a trans-dominant, non-degradable form of IkBa (IkBa (32A/36A)) under control of the macrophage-specific SR-A promoter. A diminished lipid loading during NF-κB inhibition during foam cell formation was accompanied by increased cell death. A genome-wide expression profile of NF-kB-dependent genes during foam cell formation was established showing a widespread effect on the macrophage transcriptome. The three largest functional gene clusters identified and validated by independent techniques, were those involved in lipid metabolism, apoptosis and oxidative stress. The net result of these complex gene expression changes invoked by inhibition of NF-κB activation during lipid loading is a reduction of foam cell survival through caspase-dependent apoptosis. Thus, the NF-kB-dependent gene repertoire seems essential for sustained macrophage survival during the process of pathological lipid loading. Keywords: genetic modification, lipid loading, timecourse THP-1 cells and two different THP-1 IkB mutants (A3 and A12) were exposed to PMA to induce macrophage differentiation and subsequently loaded with oxidized LDL or vehicle for 5 or 8 days. One replicate per array, a total of 15 arrays. A common reference pool, composed of an equimolar mixture of all samples, was labeled with Cy3 and hybridized against the Cy5-labeled experimental sample.
2010-06-24 | E-GEOD-12434 | biostudies-arrayexpress
Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors.
The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.
2024-05-09 | PXD037534 | JPOST Repository
Project description:Our experiments examined T-lymphocyte numbers and effector-functions in peritoneal contamination and infection (PCI) a mouse model of sepsis. One of our main questions was how T-lymphocytes reconstitute after sepsis-induced lymphopenia. We investigated the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Sepsis is an immunological dysfunction against pathogens leading to inflammation with massive cytokine production. Simultaneously immunosuppression occurs e.g. lymphopenia, which is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. More than 50% of T-cells undergo apoptosis shortly after sepsis-induction. However, 8 days after sepsis onset, surviving mice present normal lymphocyte counts. Theoretically, T-cells could reconstitute in two different ways. Firstly, the diminished pool of T-cells is replenished by newly in thymus produced T-cells with new diverse T-cell-receptors (TCRs). Alternatively, remaining T-cells start to proliferate until reaching normal cell count. If this was the case all divided cells shared the same TCRs as primary cells. This could lead to a narrowed TCR diversity within a quantitative normalized T-cell pool and would be an explanation for the long-lasting immune incompetence. To address the question how T-cells recover from lymphopenia we applied next generation sequencing (NGS) to analyse TCR diversity in septic and healthy mice. One group of septic mice received Interleukin-7 (IL-7), an interleukin which regulates T-cell homeostasis and is a promising therapeutically approach for septic patients. 50000 sequences per mouse were analyzed and the three different groups (controls, sepsis, sepsis + IL-7 treatment) compared regarding their diversity. The sequenced raw data (fastq) are uploaded in this library.
2019-10-02 | E-MTAB-7483 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-24 | PXD038951 | Pride
Project description:TNFα is a potent cytokine to mediate inflammatory response by activation of the master transcription factor NF-kB. Endothelial cells are important participants in inflammatory responses in animals. NF-kB is a major mediator to activate endothelial cells by inducing multiple pro-inflammatory genes in response to TNFα. NF-kB mediated gene transcription is known to accompany rapid changes in epigenetic states. However, the epigenetic landscape in response to the cytokine challenge TNFα in mouse endothelial cells has not been described. Our approach characterized the epigenetic profiles on a genome-wide scale and mapped putative active enhancers in primary mouse aortic endothelial cells.
2023-03-01 | E-MTAB-12212 | biostudies-arrayexpress
Project description:Transcription profiling by high throughput sequencing of sepsis survival and death
2025-01-24 | E-GEOD-63042 | ExpressionAtlas