Lymphotoxin Beta Receptor Activity in Fibroblasts Regulates Collagen Synthesis and is Crucial for Lung Fibrosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314060 | GEO | 2026/07/25
REPOSITORIES: GEO
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Project description:Lymphotoxin Beta Receptor Activity in Fibroblasts Regulates Collagen Synthesis and is Crucial for Lung Fibrosis
| PRJNA1389902 | ENA
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:Deficiency of the Collagen Endocytic Receptor MRC2 Accelerates Mouse Lung Fibroblast Proliferation
| PRJNA1233307 | ENA
Project description:Fibrosis is the end-stage of a maladaptive process that occurs when the body's normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAMD), the most common cause of central vision loss in people over the age of 50. The cellular sources of excess extracellular matrix contributing to subretinal fibrosis are unknown, as is the heterogeneity of cells involved in the fibrotic process. Here we identify cells contributing to subretinal fibrosis by using Col1a1-YFP reporter mice to non-invasively image collagen production in real-time in vivo in two disease models, 1) a resolving retinal injury model and 2) a fibrotic model of subretinal disease. We create a collagen-producing eye cell atlas for subretinal injury and demonstrate subretinal fibroblast heterogeneity in healthy, resolving and fibrotic tissue. We identify distinct molecular characteristics of general repair/resolving fibroblast populations versus pathogenic pro-fibrotic collagen-producing fibroblasts. Integration of this collagen-producing eye cell atlas with a published collagen-producing lung cell atlas shows conserved pro-fibrotic fibroblasts in both organs, yet also uncovers novel tissue-specific fibroblast populations unique to subretinal fibrosis. A Fap+Fgl2+ fibroblast population significantly expands in subretinal fibrosis that expresses the highest levels of collagens and distinctively expresses ECM components periostin, col15a1 and col6a5. Immunolabelling of mouse and human-donor eye tissue support the fibroblastic expression and peri-vascular location of periostin as clearly distinguishing between bona-fide fibrosis and early disease in nAMD. Our collagen-producing eye cell atlas is a valuable resource for studying distinct fibroblast subsets in homeostasis, early injury and fibrosis
2026-06-23 | GSE318755 | GEO
Project description:Collagen deposition is a key process during idiopathic pulmonary fibrosis (IPF); however, little is known about the dynamics of collagen formation during disease development. Tissue samples of early stages of human disease are not readily available and it is difficult to identify changes in collagen content, since standard collagen analysis does not distinguish between 'old' and 'new' collagen. Therefore, the current study aimed to (i) investigate the dynamics of new collagen formation in mice using bleomycin-induced lung fibrosis in which newly synthesized collagen was labelled with deuterated water and (ii) use this information to identify genes and processes correlated to new collagen formation from gene expression analysis. Lung fibrosis was induced in female C57BL/6 mice by bleomycin instillation and sacrificed. Animals were sacrificed at 1 to 5 weeks after fibrosis induction. Collagen synthesized during the week before sacrifice was labelled with deuterium by providing mice with deuterated drinking water. After sacrifice, lung tissue was collected for microarray analysis, determination of new collagen formation, and histology. Deuterated water labelling showed a strong increase in new collagen formation already during the first week after fibrosis induction and a complete return to baseline at five weeks. Correlation of new collagen formation data with gene expression data revealed fibrosis specific processes, of which proliferation was an unexpected one. This was confirmed by measuring cell proliferation and collagen synthesis simultaneously using deuterated water incorporation. Furthermore, new collagen formation strongly correlated with gene expression of e.g. elastin, tenascin C, MMP-14, lysyl oxidase, and type V collagen. These data demonstrate, using a novel combination of technologies, that proliferation and extracellular matrix production are correlated to the core process of fibrosis, i.e. the formation of new collagen. In addition, it identified genes directly correlated to fibrosis, thus providing more insight into the aetiology of IPF. Total RNA was obtained from mouse lungs at timepoint 0 as a control (n = 7) or timepoints 1 (n = 7), 2 (n = 6), 3 (n = 6), 4 (n = 6) or 5 (n = 6) weeks after bleomycin-instillation to induce lung fibrosis.
2013-05-26 | E-GEOD-37635 | biostudies-arrayexpress
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
Project description:Tregs with multifaceted functions suppress anti-tumor immunity by signaling surrounding cells. Tregs use the surface LTa1b2 to preferentially stimulate LTbR nonclassical NFkB signaling on both tumor and LECs to accelerate tumor growth and metastasis. Selectively targeting LTβR nonclassical NFkB pathways on both tumors and LECs cocultured with Tregs, inhibits tumor growth and migration in vitro. Leveraging in vivo Treg LTa1b2 interactions with LTβR on tumor and LECs, transfer of WT but not LTa-/- Tregs promotes B16F10 melanoma growth and tumor cell-derived chemokines in LTβR-/- mice; and increases SOX18 and FLRT2 in lymphatic vessels of LTbR-/-melanoma. Blocking the nonclassical pathways suppresses tumor growth and lymphatic metastasis by reducing chemokine production, restricting Treg and MDSC recruitment to tumors, and retaining intratumoral IFNg+ CD8 T cells. Our data reveals that Treg LTa1b2 promotes LTbR nonclassical NFkB signaling in tumor cells and LECs providing a rational strategy to prevent Treg promoted tumor growth and metastasis. Best regards
2024-11-05 | GSE270960 | GEO
Project description:Type I Collagen and Foxf1 expressing double transgenic mice that were labeled for green flourescent protein (GFP) and tdTomato reporters, respectively, were used to sort out three populations. We found that mesenchymal populations which expressed both type I collagen and Foxf1 also expressed high levels of Gli and this population carried a Col14a1 fibroblast signature while the type I collagen expressing MCs that did not express Foxf1 expressed high levels of integrin alpha 8 and carried a Col13a1 fibroblast signature.
2021-11-03 | GSE176476 | GEO