Stimulation of LTβR on human fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146536 | GEO | 2020/03/07
REPOSITORIES: GEO
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Project description:Stimulation of LTβR on human fibroblasts
| PRJNA610825 | ENA
Project description:LTβR signaling is crucial for immune development, homeostasis, and inflammation. To identify protein determinants that control the quality of LTβR function, we use a novel proteomics approach to identify EWS as a novel signaling component of this pathway. LTβR signaling protein, TRAF3, controls the protein binding activity of EWS via formation of mutually exclusive protein-protein interactions. With transcriptomics and knockdown experiments we identify several pro-inflammatory genes with induction kinetics that are controlled by EWS during LTβR signaling. Given the link between gene induction responsiveness and mRNA decay, we show EWS controls the decay of these transcripts.
2019-03-01 | GSE110102 | GEO
Project description:Lymphotoxin β-receptor-signalling orchestrates lymphoid neogenesis and subsequent tertiary lymphoid structures (TLS) associated with severe chronic inflammatory diseases spanning multiple organ systems. How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanism(s) regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. Here we demonstrate increased lymphotoxin expression of LTbR-ligands on myeloid and adaptive and innate immune-cells, enhanced non-canonical NF-κB signalling and enrichment of LTβR-target gene expression in epithelial cells of lungs from patients and mice with smoking-associated chronic obstructive pulmonary disease (COPD). Accordingly, Therapeutic inhibition of LTβR-signalling in young and aged mice with COPD disrupted TLS, reverted lung tissue destruction, airway-fibrosis and systemic muscle wasting. Mechanistically, we identified that LTβR-signalling blockade leads to diminished cell-death, concomitantly reactivated endogenous Wnt/β-catenin-signalling in alveolar epithelial cells and reduced TGFβ-signalling in airways. These findings highlight LTβR as a viable therapeutic target against TLS induced tissue damage that translates into novel anti-inflammatory, regenerative strategies to treat COPD.
2020-07-10 | GSE125521 | GEO
Project description:How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanisms regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. To study the mechanisms underlying LTβR-inhibition, a transcriptional analysis was performed on lung tissue from B6 mice exposed to cigarette smoke for 6 months and treated therapeutically with LTβR-Ig from 4 to 6 months compared to mice exposed to cigarette smoke for 6 months and treated with control Ig from 4 to 6 months and filtered air control. Single-cell RNA-Seq identified 24 distinct cell populations across >20,000 cells in lungs with distinct changes occurring upon cigarette smoke exposure and LTβR-Ig treatment.
2020-07-10 | GSE151674 | GEO
Project description:Continuous thymic homing of hematopoietic progenitor cells (HPCs) via the blood is critical for normal T cell development. However, the nature and the differentiation program of the specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here, using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTβR) directly controls thymic ECs to guide HPC homing. Interestingly, T cell deficiency or conditional ablation of T-cell-engaged LTβR signaling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTβR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTβR is required for T cell regeneration upon irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing.
2017-02-09 | GSE83114 | GEO
Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course for each cell type (wt, relA-/-, relB-/-) two time points were analysed (0h as control and 10h) using 3 technical replicates resulting in 18 samples in total
2008-12-17 | E-GEOD-11963 | biostudies-arrayexpress
Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course
2008-12-18 | GSE11963 | GEO
Project description:As a specialized subset of intestinal epithelial cells (IECs), goblet cells (GCs) play an important role during the antibacterial response via mucin production. However, the regulatory mechanisms involved in GC differentiation and function during infection, particularly the role of immune cell-IEC crosstalk, remain largely unknown. Here, using VillinΔLtbr conditional knockout mice, we demonstrate that LTβR, expressed on IECs, is required for GC hyperplasia and mucin 2 (MUC2) expression during Listeria infection for host defense but not homeostatic maintenance in the naïve state. Analysis of single gene-deficient mice revealed that the ligand lymphotoxin (LT) but not LIGHT and type 3 innate lymphoid cells (ILC3s) but not conventional T cells are required for MUC2-dependent Listeria control. Conditional deficiency of LT in ILC3s further confirmed the importance of LT signals derived from ILC3s. Lack of ILC3-derived LT or IEC-derived LTβR resulted in defective expression of genes related to GC differentiation but was not correlated with IEC proliferation and cell death, which were found to be normal by Ki-67 and Annexin V staining. In addition, the alternative NF-κB signaling pathway (involving RelB) in IECs was found to be required for the expression of GC differentiation-related genes and Muc2 and required for the anti-Listeria response. Therefore, our data together suggest a previously unrecognized ILC3-IEC interaction and LT-LTβR-RelB signaling axis governing GC differentiation and function during Listeria infection for host defense.
2020-05-26 | GSE150071 | GEO
Project description:The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin β Receptor (LTβR), a core member of the Tumor Necrosis Factor (TNF)/TNF Receptor (TNFR) superfamily is known to play an important role in this process. However, LTβR functions in the pathophysiological alterations and molecular mechanisms of liver regeneration are so far ill-characterized. Interestingly, LTβR / mice suffered from increased and prolonged liver tissue damage after 70 % hepatectomy (PHx), a finding accompanied by elevated alkaline phosphatase levels and deregulated bile acid (BA) homeostasis. Pronounced differences in the expression patterns of genes relevant for BA synthesis and recirculation were observed. Transcriptome analysis revealed a marked disparity in gene expression programs in LTβR / vs. WT liver tissue, where gene ontology (GO) terms related to transcription, gene expression and metabolic pathways were over-represented in the latter. In addition, murinoglobulin 2 (Mug2), a gene product to date not implicated in liver regeneration, was identified as one of the most differentially regulated genes after PHx in WT compared to LTβR / and TNFRp55-/- livers. LTβR and TNFRp55 share downstream signaling elements. TNFRp55 is known to also play an important role in liver regeneration after PHx. Therefore, LTβR / mice were treated with Etanercept to create mice functionally deficient in both signaling pathways. Strikingly, the combined blockade of TNFR and LTβR signaling leads to complete failure of liver regeneration resulting in death within 24 to 48 hours after PHx. LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signaling renders liver regeneration impossible.
2024-02-25 | GSE74531 | GEO
Project description:The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin β Receptor (LTβR), a core member of the Tumor Necrosis Factor (TNF)/TNF Receptor (TNFR) superfamily is known to play an important role in this process. However, LTβR functions in the pathophysiological alterations and molecular mechanisms of liver regeneration are so far ill-characterized. Interestingly, LTβR / mice suffered from increased and prolonged liver tissue damage after 70 % hepatectomy (PHx), a finding accompanied by elevated alkaline phosphatase levels and deregulated bile acid (BA) homeostasis. Pronounced differences in the expression patterns of genes relevant for BA synthesis and recirculation were observed. Transcriptome analysis revealed a marked disparity in gene expression programs in LTβR / vs. WT liver tissue, where gene ontology (GO) terms related to transcription, gene expression and metabolic pathways were over-represented in the latter. In addition, murinoglobulin 2 (Mug2), a gene product to date not implicated in liver regeneration, was identified as one of the most differentially regulated genes after PHx in WT compared to LTβR / and TNFRp55-/- livers. LTβR and TNFRp55 share downstream signaling elements. TNFRp55 is known to also play an important role in liver regeneration after PHx. Therefore, LTβR / mice were treated with Etanercept to create mice functionally deficient in both signaling pathways. Strikingly, the combined blockade of TNFR and LTβR signaling leads to complete failure of liver regeneration resulting in death within 24 to 48 hours after PHx. LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signaling renders liver regeneration impossible.
2024-02-25 | GSE67263 | GEO