Murine bronco alveolar lavage fluid from wild type and mannose receptor knock out mice, unchallenged and LPS challenged
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Lung
SUBMITTER: 
Kirstine Nørregaard
LAB HEAD: Niels Behrendt
PROVIDER: PXD049201 | Pride | 2024-04-17
REPOSITORIES: Pride
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Project description:Rationale: Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. Objectives: To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo. In seven healthy humans sterile saline was instilled into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done (Affymetrix HG-U133 Plus 2.0) on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals.
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Project description:Thirty female BALB/c mice of 6-8 weeks of age were purchased from Charles River (Montreal, QC, Canada) and divided randomly into control (n=15) and treated (n=15) groups. Mice were maintained on an egg free diet in the pathogen-free conditions at the University of Guelph Central Animal Facility. Animals were maintained between 2224°C and at a relative humidity of 4050%. The light-to-dark cycle was maintained at 12 h from 7 AM to 7 PM. All of the animal experiments were approved by the University of Guelph Animal Care Committee according the Canadian Council on Animal Care (CCAC) guidelines.Mice were exposed to intra-gastric gavage (i.g.) twice every week for 5 weeks with OVM (1 mg/100 μl) and 10 μg of cholera toxin adjuvant. An amino acid (Sigma, St. Louis, MO) solution of 10 μg/μl (100 μl per mouse with 10 μg of cholera toxin) was used as a negative control. The amino acids were mixed accordingly to match the OVM amino acid composition. Five weeks after the first sensitization, mice were challenged by i.p. injection with 1 mg of OVM in 50 μl of sterile water and aluminum hydroxide (50 μl, 2% Alhydrogel) adjuvant (Superfos Biosector, Denmark), to induce an immediate type-1 hypersensitivity reaction. The anaphylactic responses were visualized and scored depending on the response of the individual mice in each of the treated and control groups. After 40 min, mice were euthanized with CO2 and partial spleen tissue samples were collected in RNAlater solution for microarray experiment (Ambion Inc., TX, USA). Spleen samples in RNAlater solution were kept at 4oC overnight prior to long term storage at -80oC.
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Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
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Project description:Background: It has been shown previously that administration of Francisella tularensis (Ft) LVS lipopolysaccharide (LPS) protects mice against subsequent challenge with Ft LVS and blunts the pro-inflammatory cytokine response. Methods: To investigate further the molecular mechanisms that underlie Ft LVS LPS-mediated protection, we profiled global hepatic gene expression following Ft LVS LPS or saline pretreatment and subsequent Ft LVS challenge using Affymetrix arrays. Results: A large number of genes (> 3000) were differentially expressed at 48 hours post-infection. The degree of modulation of inflammatory genes by infection was clearly attenuated by LPS-pretreatment in the surviving mice. However, LPS alone had a subtle but significant effect on the gene expression profile of the uninfected mice. By employing gene set enrichment analysis, we discovered significant up-regulation of peroxisome proliferator activated receptors (PPARs) and their target genes in LPS-treated liver. Conclusions: We hypothesize that the LPS-induced blunting of pro-inflammatory response in mouse is, in part, mediated by PPARs (alpha and gamma). Experiment Overall Design: Two groups of 9 mice each were used for this experiment. 48 hours prior to Ft LVS challenge, mice were injected i.p. with either 100 ng of Ft LVS LPS or an equivalent volume of saline. On the day of challenge, 3 saline- and 3 Ft LVS LPS-pretreated animals were sacrificed (uninfected controls), while all remaining mice were challenged i.p. with ~4-5 X 105 Ft LVS. Ft LVS-challenged mice were sacrificed (in groups of 3) at 24 and 48 hours post-infection.
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