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Inhibition of LTβR-signalling blocks epithelial apoptosis and activates endogenous Wnt-induced regeneration

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE125521 | GEO | 2020/07/10

REPOSITORIES: GEO

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Analysis of lung transcriptomic changes following inhibition of LTβR-signalling in cigarette smoke exposed mice

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

Intestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function - Intestinal fibroblasts

Project description:Innate lymphoid cells (ILC) in the small intestine govern immune homeostasis and protect the host against gut pathogens. While distinct cell-intrinsic signals have been identified that determine ILC development and differentiation, it has remained unclear which cell population regulates ILC sustenance. Using unbiased single cell RNA transcriptomic analysis of intestinal fibroblasts, we have identified a specialized Ccl19-expressing fibroblastic reticular cell (FRC) population that underpins solitary intestinal lymphoid tissue (SILT) structures including cryptopatches and isolated lymphoid follicles. Conditional ablation of lymphotoxin-β receptor (LTβR) signalling in SILT FRC impeded the maturation of isolated lymphoid follicles and blocked ILC maintenance through the downregulation of IL-7, consequently resulting in the elevated susceptibility to bacterial infection. Moreover, specific Ltbr ablation in FRC during adulthood revealed that constant LTβR-dependent FRC-ILC interaction is required to maintain SILT structures and ILC populations. Taken together, our study unveils a critical intestinal FRC niche that secures protective gut immunity.

2022-02-12 | E-MTAB-10638 | biostudies-arrayexpress

Intestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function - Innate lymphoid cells

2022-02-12 | E-MTAB-10645 | biostudies-arrayexpress

Lymphoid Follicle Spatial Transcriptomics Resolve an Emphysema-Specific B Cell Signature in COPD

Project description:Using Geomx's Digital Space Profiling method for WTA RNA transcriptomics in lung tertiary lymphoid structures (TLS, follicles), we assessed paraffin-embedded and OCT-embedded lung sections from 48 patients, which were classified as Never Smoker Controls (NSC, n=8), Smoker Controls (SC, n=13), and COPD GOLD1-4 patients (n=27 patients). we identified 19 patients with tertiary lymphoid structures (TLS), distributed as 13 COPD patients and 6 SC subjects, with 115 TLS data used for the final data analysis.

2023-11-21 | GSE237120 | GEO

LTβR controls thymic portal endothelial cells for hematopoietic progenitor cell homing and T cell regeneration

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

RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

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

Type 3 innate lymphoid cells direct goblet cell differentiation via the LT-LTβR pathway during Listeria infection

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

Tumoral and stromal hMENA isoforms influence tertiary lymphoid structure localization and predict response to immunocheckpoint blockade in lung cancer patients

Project description:The advent of immunotherapy in the clinical practice of non-small cell lung cancer (NSCLC) have highlighted the impact of the tumor immune microenvironment in the control of the tumor progression, as well as in the response to immune checkpoint blockade (ICB) therapy. Tertiary Lymphoid Structures (TLS), determinants of antitumor immunity, are associated with a favorable clinical outcome in NSCLC patients and with the effectiveness of ICB in several tumors. The actin regulatory protein hMENA undergoes tissue-specific splicing, with tumors expressing hMENA11ahigh/ stromal fibronectin (FN1)low related to early N0 NSCLC patients with a favorable prognosis. hMENA/hMENA∆v6 is overexpressed in pro-tumoral CAFs related to the subtype of immunosuppressive ECM-my-CAF Herein, by analyzing the pattern of hMENA isoform expression in tumor cells and CAFs, we highlighted the role of hMENA as a crucial factor in the communication among tumor cells CAFs, T and B cells. Mechanistically, we demonstrated that in NSCLC cell lines hMENA11a increases the expression of the TLS regulator LTβR, reduces the FN1 expression and favors CXCL13 production by tissue resident T cells. Conversely in CAFs, hMENA/hMENAΔv6 inhibits the NF-kB pathway downstream to LTβR and the secretion of CXCL13, crucial in TLS formation. Of clinical relevance, our experimental data support our finding in primary tumors that TLS localized within the tumor area (TLS-IT) are predictive of a longer disease-free survival in N0 NSCLC patients and are accompanied by the maturation of B cells in the tumor tissue. TLS-IT associate with paucity of hMENA positive CAFs, low stromal FN1 and high hMENA11a tumor cell expression. To translate these results in a clinical setting of ICB treated patients, we identified a signature based on the pattern of hMENA isoforms, FN1 and LTβR expression that may discriminate NSCLC patients responding or not-responding to ICB.

2023-08-30 | GSE217451 | GEO

Stimulation of LTβR on human fibroblasts

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

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop [10X Genomics]

Project description:The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

2022-11-02 | GSE198079 | GEO

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