Inhibition of LTβR-signalling blocks epithelial apoptosis and activates endogenous Wnt-induced regeneration
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PROVIDER: PRJNA516667 | ENA |
REPOSITORIES: ENA
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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:Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
| S-EPMC7718297 | biostudies-literature
Project description:LTβR signaling is crucial for immune development, homeostasis, and inflammation. To identify new factors that influence the quality of LTβR function, we combined transcriptomics with WGCNA.
2020-03-07 | GSE146536 | GEO
Project description:Analysis of lung transcriptomic changes following inhibition of LTβR-signalling in cigarette smoke exposed mice
| PRJNA636811 | ENA
Project description:Stimulation of LTβR on human fibroblasts
| PRJNA610825 | ENA
Project description:TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression
| PRJEB55174 | ENA
Project description:TGFβ-induced lncRNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression
| PRJEB61535 | ENA
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:ObjectivesThe relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer.DesignPathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC).ResultsAKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling.ConclusionsOur findings link LTβR and oncogenic AKT signalling in the development of ICC.
| S-EPMC5036232 | biostudies-literature