CRel Expression Regulates Distinct Transcriptional and Functional Profiles Driving Fibroblast Matrix Production in Systemic Sclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE151469 | GEO | 2020/05/30
REPOSITORIES: GEO
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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:cRel Expression Regulates Distinct Transcriptional and Functional Profiles Driving Fibroblast Matrix Production in Systemic Sclerosis
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Project description:The sparse vascularity of Pancreatic Ductal Adenocarcinoma (PDAC) presents a mystery: what prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of non-canonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.
2023-12-01 | GSE247072 | GEO
Project description:Microarray analysis was used to show that in gingival fibroblasts essentially all TGFB1 responsive genes were blocked by TAK inhibition Affymetrix Human Gene 1.0 ST arrays were used to identify differential gene expression changes bewteen samples.
2015-02-26 | E-GEOD-65069 | biostudies-arrayexpress
Project description:The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-κB) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-κB subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-κB pathway, paving the way for subunit-targeted immunotherapies.
2024-03-28 | GSE239700 | GEO
Project description:The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-κB) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-κB subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-κB pathway, paving the way for subunit-targeted immunotherapies.
2024-03-28 | GSE239698 | GEO
Project description:The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-κB) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-κB subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-κB pathway, paving the way for subunit-targeted immunotherapies.
2024-03-28 | GSE239703 | GEO
Project description:OT-1 Transgenic CD8 T-cells were isolated from spleens of WT, PKCθ theta KO, and p50 cRel DKO mice. The T-cells were either cultured with non-pulsed DC (WT only and signified as "WT - UN") or with BMDCs pulsed with the OVA peptide SIINFEKL (N4) (WT, PKCθ theta KO, and p50 cRel DKO and signified as 'genotype - N4') at a ratio of 1:10 (DC:T-cell) for 18 hours. DCs then were depleted from the culture and RNA was made from the T-cells to measure gene expression at the early / late stage of T-cell activation
2014-12-01 | GSE61758 | GEO
Project description:cRel is a transcription factor critical for the development of Tregs in the thymus. We examined the impact the lack of cRel has on Tregs at different stages of ontogeny (thymic pre-Tregs, thymic 'de novo' Tregs and mature spenic Tregs).
2021-05-29 | GSE154166 | GEO
Project description:NF-kB plays a crucial role in immunity to infection. This transcription factor consists in different combinatory homo- and hetero-dimers of the five members of the Rel family. cRel/p50-containing dimers have been involved in the development and function of the immune cells. However, the transcriptional roles of these two subunits still remain poorly explored in innate immune cells. By a multiple approach integrating ex vivo genomic analysis and an in vivo experimental study, we have investigated the consequences of the combined absence of cRel and p50 subunits of NF-kB in the innate response to infection. We have performed gene profiling of cRel-/-p50-/- (DKO) and wild type (WT) peritoneal macrophages stimulated with endotoxin for 2, 6 or 18 hours.
2012-11-21 | E-MEXP-3446 | biostudies-arrayexpress