Immune cell transcriptional programs severe allergic airway inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244649 | GEO | 2024/05/01
REPOSITORIES: GEO
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Project description:Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns (PAMPs) reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3’-5’)-cyclic dimeric guanosine monophosphate (c-di-GMP) for a variety of activities. Here we report that c-di-GMP comprehensively regulates both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs, while decreasing the number and repopulation capacity of long-term hematopoietic stem cells (LT-HSCs). Furthermore, we show that type I IFN acts as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while TGF-β1 is required for c-di-GMP-dependent splenic HSPC expansion. Our results define novel machinery underlying dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling. Ten-week-old mice were intraperitoneally administered PBS or 200 nmol c-di-GMP, and CD150+ CD41- CD48- CD34- Flt3- LSK cells of pooled bone marrow from 10 mice per group were sorted 3 days later. mRNA was then extracted using RNeasy micro (Qiagen). Likewise, CD45- Ter-119- CD31- CD140a+ CD51+ MSCs and CD45- Ter119- CD31+ endothelial cells from c-di-GMP-treated or untreated mice were sorted and mRNA was extracted. cDNA was synthesized from mRNA and hybridized to gene chip Mouse60k (Agilent Technologies) and expression levels analyzed.
2015-02-13 | E-GEOD-65905 | biostudies-arrayexpress
Project description:This project investigates the mechanisms that underlie asthma-related phenotypes associated with allergen exposure. See http://www.hopkins-genomics.org/asthma/asthma006/index.html The goal of the experiment was to identify genes that change their levels of expression as a consequence of challenge with allergen. The experiments utilized a murine model of human asthma that employed BALB/CJ mice. In this particular sensitization-challenge protocol, the response produced by BALB/CJ mice is representative of a majority of the mouse strains tested. The antigen complex used to sensitize and challenge the mice was ragweed pollen an allergen that is highly relevant to human disease. Keywords: time series, allergen
2005-08-24 | GSE3184 | GEO
Project description:An important feature of human asthma and animal models of asthma is airway hyperresponsiveness. The symptoms of asthma are a narrowing of the airways caused by edema and the influx of inflammatory cells. The aim of this project is to determine the temporal relationship between gene expression and airway allergen challenge. 4 weeks old BALB/CJ mice were challenged on days 0,3,10 and 17 with PBS and ragweed pollen protein plus Alum. Keywords: time series, allergen
2003-07-16 | GSE483 | GEO
Project description:RATIONALE: In a mouse model of maternal transmission of asthma risk (J. Immunol 170:1683, 2003), baby mice of asthmatic (As), but not normal (Nrm), mothers show increased susceptibility to allergy. We previously showed that adoptive transfer to normal baby mice of dendritic cells (DCs) harvested from asthma-susceptible but allergen-naïve neonates reproduces the increased susceptibility to asthma. Hence, the maternal effect is mediated by altered neonatal DCs, which skew immune responses towards a pro-allergic Th2 phenotype. To identify potential molecular mechanisms, we performed epigenomic profiling of isolated neonatal DCs. METHODS: BALB/c mice were sensitized by 2 i.p. injections of ovalbumin (OVA) in alum and repeatedly challenged with OVA aerosols (As) prior to mating with normal males. Purified splenic CD11c+ DCs of 14-day old allergen-naïve offspring from these As and control Nrm mothers were isolated using magnetic beads. Methylation profiles of genomic DNA were obtained using Switchgear epigenomic chip arrays. After normalization and background correction analysis using significance analysis for microarrays (SAM) and ANOVA was performed. RESULTS: We identified 300 to 6000 (depending on stringency) chromosomal regions with significantly different methylation status, (2 â 10 fold). Clustering methods and pathway analysis identified several interrelated gene groups that merit further study. CONCLUSION: Maternal asthma causes multiple significant epigenetic changes in neonatal dendritic cells. Keywords: Dendritic cells, genomic DNA, DNA methylation, allergy, asthma The analysis includes 9 samples of genomic DNA from isolated splenic CD11c+ dendritic cells (>95% pure) per group. The two groups are neonates born to mothers with induced allergy to ovalbumin, and normal control neonates. All neonates are genetically and environmentally identical, and allergen-naive.
2010-06-24 | E-GEOD-13380 | biostudies-arrayexpress
Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice
2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress
Project description:Using a human model of asthma exacerbation, we compared the airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA-sequencing frameworks. In response to allergen challenge, the airway epithelium in asthmatics was highly dynamic and upregulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. Asthmatics also had a unique mucosal immune profile, characterized by IL9-expressing pathogenic TH2 cells and enrichment of DC2 (CD1C) and CCR2-expressing monocyte-derived cells (MC) after allergen, with upregulation of genes that promote pathologic airway remodeling. In contrast, controls were enriched for macrophage-like MC that upregulated tissue repair programs after allergen challenge, suggesting these populations may protect against asthmatic airway remodeling. These findings reveal a novel TH2-mononuclear phagocyte-epithelial interactome unique to asthmatics, suggesting that pathogenic effector circuits and the absence of pro-resolution programs drive structural airway disease in response to type 2 inflammation.
2023-02-24 | GSE193816 | GEO
Project description:Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses are not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we have characterized a sub-population of Th2 cells that secretes IL-9 as an obligate effector cytokine. IL-9-secreting cells have a resident memory T cell phenotype and blocking IL-9 during a recall challenge significantly diminishes airway inflammation and airway hyperreactivity. T cells secrete IL-9 in response to allergen recall and secretion is amplified by IL-33. Using scRNA-seq and scATAC-seq, we define the cellular identity of a distinct populations of T cells with pro-allergic cytokine patterns. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multi-cytokine producing cell population is required for an allergen recall response.
2022-01-31 | GSE190795 | GEO
Project description:Signaling via the arylhydrocarbon receptor (AhR) is thought to contribute to exacerbation of allergic asthma by anthropogenic pollution. The physiological role of AhR and its downstream targets CYP1 family members upon exposure to aeroallergens remain unknown. We seek to characterize the role of the AhR pathway for the regulation of allergic airway inflammation (AAI). We employed knockout animals of the AhR and its downstream target cytochrome P450 enzymes CYP1A1, CYP1A2 and CYP1B1 and subjected them to preclinical allergic asthma models (ragweed and house dust mite) to assess the role of AhR and CYP1 family members in allergic airway inflammation. Histological, transcriptional and functional assays were used to uncover relevant cell types and mechanistic insights. In the ragweed model, AhRKO/KO and CYP1B1KO/KO but not CYP1A2 KO/KO or CYP1A2KO/KO animals showed exacerbation of AAI including elevated infiltration of cells in the bronchoalveolar lavage fluid and increased serum levels of IgE and allergen-specific IgG1. AhR KO/KO and CYP1B1KO/KO animals showed also more severe reactions in HDM-induced allergic AAI. Bone marrow chimeras as well as qPCR analysis and immune fluorescence histology indicate that expression of CYP1B1 in non-hematopoietic cells – presumably lung epithelial cells – is necessary to prevent exacerbation of HDM-induced AAI. Mechanistically, we show that CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and thus potentially to deprivation from endogenous AhR ligands. Transcriptional analysis of primary lung epithelial cells indicates a functional link of the AhR to regulation of circadian clock genes at baseline and massive alteration of gene expression upon allergen exposure.
2022-05-23 | GSE158715 | GEO
Project description:Antigen encounter directs CD4+ T cells to differentiate into T-helper or -regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern -helper versus -regulatory fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells developed enhanced Th2 and Th9 inflammation and pathophysiological features of atopic asthma upon allergen exposure. Following T cell activation, Cul5 formed a complex with CIS and pJak1. Loss of Cul5 function resulted in reduced ubiquitylation and increased stability of pJak1, elevated STAT6 activity, and a reduced threshold for IL-4 receptor signaling. In keeping with this, Cul5-deficient T cells deviated from Treg to Th9 differentiation in low IL-4 conditions. These data support that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.
2022-06-09 | PXD028492 | Pride
Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma.
2015-03-01 | GSE57772 | GEO