Aryl hydrocarbon receptor (AHR)-dependent protection against lung vascular leakage in viral infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE203427 | GEO | 2023/05/23
REPOSITORIES: GEO
Similar Datasets
Project description:We found that a dose of influenza (5,000 pfu of recombinant influenza A/WSN/33 (rWSN) H1N1 virus strain) that resulted in 50% mortality in wildtype littermate control mice showed minimal mortality in Irgm1-/- mice, indicating that Irgm1 deficiency was protective during influenza infection. This protective effect was dependent on the Type I interferon receptor Ifnar. We performed transcriptional profiling to identify molecular mechanisms associated with protection from influenza infection in Irgm1-/- lung. Both male and female mice were used at 8-12 weeks of age. Lung gene expression was assessed by RNA-seq at the following times post-influenza infection: Day 3 (early time point, early histological damage present in control mice), Day 6 (intermediate time point, late histological damage present in control mice) and Day 10 (late time point, morbidity and mortality present in control mice).
2017-08-08 | E-MTAB-5337 | biostudies-arrayexpress
Project description:We have identified the apelin-APJ axis as a mechanism of protection mediated by AHR signalling in lund=g endothelial cells. This RNAseq experiment will compare the effects of apelin receptor blockade on endothelial and epithelial responses in the lung during influenza infection.
2023-05-23 | GSE225958 | GEO
Project description:The blood and lymphatic vasculature is lined by functionally specialised endothelial cells (ECs). In the intestine, ECs act as an essential physical barrier, controlling nutrient transport, facilitating tissue immunosurveillance, and coordinating angiogenesis and lymphangiogenesis to ensure appropriate tissue perfusion and drainage. Conversely, endothelial maladaptation can lead to pathological angiogenesis and the perpetuation of inflammation in chronic inflammatory diseases. However, whether enteric ECs actively engage in the regulation of intestinal homeostasis and pathology through integration of environmental cues is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, acts as critical node for EC-sensing of dietary and microbial metabolites. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs, identifying transcriptional networks and putative biological roles across endothelial subtypes. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting quiescence and vasculoprotection. Endothelial AHR-deficiency in mice resulted in cellular activation, proliferation, and initiation of angiogenic pathways disrupting tissue homeostasis. In human ECs, AHR signalling promoted quiescence through cell cycle arrest and tempered endothelial inflammatory responses. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling serves to promote homeostasis and prevent aberrant inflammatory responses at the intestinal barrier.
2023-07-12 | GSE224806 | GEO
Project description:The blood and lymphatic vasculature is lined by functionally specialised endothelial cells (ECs). In the intestine, ECs act as an essential physical barrier, controlling nutrient transport, facilitating tissue immunosurveillance, and coordinating angiogenesis and lymphangiogenesis to ensure appropriate tissue perfusion and drainage. Conversely, endothelial maladaptation can lead to pathological angiogenesis and the perpetuation of inflammation in chronic inflammatory diseases. However, whether enteric ECs actively engage in the regulation of intestinal homeostasis and pathology through integration of environmental cues is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, acts as critical node for EC-sensing of dietary and microbial metabolites. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs, identifying transcriptional networks and putative biological roles across endothelial subtypes. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting quiescence and vasculoprotection. Endothelial AHR-deficiency in mice resulted in cellular activation, proliferation, and initiation of angiogenic pathways disrupting tissue homeostasis. In human ECs, AHR signalling promoted quiescence through cell cycle arrest and tempered endothelial inflammatory responses. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling serves to promote homeostasis and prevent aberrant inflammatory responses at the intestinal barrier.
2023-07-12 | GSE201788 | GEO
Project description:The blood and lymphatic vasculature is lined by functionally specialised endothelial cells (ECs). In the intestine, ECs act as an essential physical barrier, controlling nutrient transport, facilitating tissue immunosurveillance, and coordinating angiogenesis and lymphangiogenesis to ensure appropriate tissue perfusion and drainage. Conversely, endothelial maladaptation can lead to pathological angiogenesis and the perpetuation of inflammation in chronic inflammatory diseases. However, whether enteric ECs actively engage in the regulation of intestinal homeostasis and pathology through integration of environmental cues is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, acts as critical node for EC-sensing of dietary and microbial metabolites. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs, identifying transcriptional networks and putative biological roles across endothelial subtypes. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting quiescence and vasculoprotection. Endothelial AHR-deficiency in mice resulted in cellular activation, proliferation, and initiation of angiogenic pathways disrupting tissue homeostasis. In human ECs, AHR signalling promoted quiescence through cell cycle arrest and tempered endothelial inflammatory responses. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling serves to promote homeostasis and prevent aberrant inflammatory responses at the intestinal barrier.
2023-07-12 | GSE201785 | GEO
Project description:The blood and lymphatic vasculature is lined by functionally specialised endothelial cells (ECs). In the intestine, ECs act as an essential physical barrier, controlling nutrient transport, facilitating tissue immunosurveillance, and coordinating angiogenesis and lymphangiogenesis to ensure appropriate tissue perfusion and drainage. Conversely, endothelial maladaptation can lead to pathological angiogenesis and the perpetuation of inflammation in chronic inflammatory diseases. However, whether enteric ECs actively engage in the regulation of intestinal homeostasis and pathology through integration of environmental cues is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, acts as critical node for EC-sensing of dietary and microbial metabolites. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs, identifying transcriptional networks and putative biological roles across endothelial subtypes. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting quiescence and vasculoprotection. Endothelial AHR-deficiency in mice resulted in cellular activation, proliferation, and initiation of angiogenic pathways disrupting tissue homeostasis. In human ECs, AHR signalling promoted quiescence through cell cycle arrest and tempered endothelial inflammatory responses. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling serves to promote homeostasis and prevent aberrant inflammatory responses at the intestinal barrier.
2023-07-12 | GSE201783 | GEO
Project description:The blood and lymphatic vasculature is lined by functionally specialised endothelial cells (ECs). In the intestine, ECs act as an essential physical barrier, controlling nutrient transport, facilitating tissue immunosurveillance, and coordinating angiogenesis and lymphangiogenesis to ensure appropriate tissue perfusion and drainage. Conversely, endothelial maladaptation can lead to pathological angiogenesis and the perpetuation of inflammation in chronic inflammatory diseases. However, whether enteric ECs actively engage in the regulation of intestinal homeostasis and pathology through integration of environmental cues is currently unknown. Here, we show that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, acts as critical node for EC-sensing of dietary and microbial metabolites. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine uncovering the cellular complexity and functional heterogeneity of blood and lymphatic ECs, identifying transcriptional networks and putative biological roles across endothelial subtypes. Analyses of AHR mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting quiescence and vasculoprotection. Endothelial AHR-deficiency in mice resulted in cellular activation, proliferation, and initiation of angiogenic pathways disrupting tissue homeostasis. In human ECs, AHR signalling promoted quiescence through cell cycle arrest and tempered endothelial inflammatory responses. Together, our data provide a comprehensive dissection of the impact of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling serves to promote homeostasis and prevent aberrant inflammatory responses at the intestinal barrier.
2023-07-12 | GSE201780 | GEO
Project description:Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange between pulmonary endothelial cells (ECs) lining these vessels and the alveolar epithelium. However, the factors that control EC stress response and drive regeneration of pulmonary capillaries remain incompletely understood. Viral infections such as influenza and COVID-19 may indirectly damage lung vasculature through loss of epithelial gas exchange partners or through signaling from infiltrating immune cells. To prevent excessive tissue damage and to renew the endothelium, ECs must both withstand cellular stress and proliferate after injury. Here, we show that the transcription factor and immediate early gene Atf3 is essential for both responses in the mouse lung after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in cellular response to stress, angiogenesis, and vascular development. Endothelial loss of ATF3 results in defective alveolar regeneration: in the absence of ATF3, ECs exhibit increased apoptosis and decreased proliferation, resulting in an emphysema-like phenotype with enlarged alveolar airspaces lined with regions of lost vasculature. These data implicate ATF3 as an essential component of the vascular response to acute lung injury that is required for successful lung regeneration.
2023-05-19 | GSE213475 | GEO
Project description:Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. We have demonstrated that paladin has a predominant vascular expression pattern and shifts from endothelial to mural cells during mouse development. We have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice displayed an emphysema-like phenotype with increased alveolar air spaces and impaired lung function with obstructive changes. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that paladin is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
Proteomic analysis of Pald1 wild type and knock-out mice reveal that most of the protein expression differences are related to sex and not genotype, supporting the notion that sex can be a major factor for lung development and disease. In addition, Pald1 wild type and knock-out mice exhibit differential expression of HPGD, hydroxyprostaglandin dehydrogenase 15 (NAD), the major enzyme for degradation of prostaglandins.
2017-11-01 | PXD005625 | JPOST Repository
Project description:Introduction Epidemiological studies have shown that smoking is associated with increased incidence of severe viral infections leading to hospitalisation. Moreover, studies in experimental models have identified impaired antiviral responses and altered inflammatory responses, yet it is unclear which immune cells are involved and whether this varies over the course of infection. Methods To test how cigarette smoking affects the response to influenza viral infection over time, female BALB/c mice were exposed to cigarette smoke or air twice a day for 24-28 days and infected with H3N2 influenza or mock infection on day 21. Three and seven days after infection, changes in immune cell populations, and mRNA expression/viral clearance in lung tissue were analysed. Results Smoke-exposed mice lost significantly more weight than air-exposed controls after influenza infection, indicating that smoking resulted in more severe disease. Immune cell and lung tissue transcriptome analysis revealed that neutrophil infiltration was prolonged and macrophage activation dysregulated after infection in smoke-exposed mice compared to air-exposed controls. Expression of genes in IL-6 and interferon pathways was similarly longer active. In parallel, we observed lower clearance of viral RNA in smoke-exposed mice after infection compared to air-exposed controls, indicating ineffective antiviral responses. Adaptive immune responses were unchanged in infected smoking animals compared to nonsmoking mice. Conclusion Altogether, the data from our mouse model indicate that cigarette smoke exposure prolongs innate immune responses against influenza. The results from this study help to explain the susceptibility of current smokers to severe influenza disease.
2024-06-21 | GSE269227 | GEO