Browsing by Subject "β-glucosylceramide"

Now showing 1 - 3 of 3
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    Cord blood sphingolipids are associated with atopic dermatitis and wheeze in the first year of life
    (Elsevier, 2022) Hoji, Aki; Kumar, Rajesh; Gern, James E.; Bendixsen, Casper G.; Seroogy, Christine M.; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    Background: Allergen-sensitized pregnant mice have increased plasma levels of the lipids β-glucosylceramides (βGlcCers) that are transplacentally transferred to the fetus, increased subsets of proinflammatory dendritic cells in the fetal liver and pup lung, and increased allergen-induced offspring lung inflammation. Objective: Our aim was to determine whether these preclinical observations extend to a human association of βGlcCers with wheeze and allergic disease in the prospective Wisconsin Infant Study Cohort. Methods: We measured 74 lipids in cord blood plasma by using mass spectrometry detection of sphingolipids, eicosanoids, and docosinoids, as well as an ELISA for 13-hydroxyoctadecadienoic acid. Lipid profiles were determined by unbiased Uniform Manifold Approximation and Projection dimensional reduction machine learning. Lipid profiles and a proinflammatory lipid index were analyzed for association with maternal allergy and childhood outcomes of wheeze, atopic dermatitis, cord blood leukocytes, and total IgE level at age 1 year. Results: Uniform Manifold Approximation and Projection analysis of lipids defined 8 cluster-specific plasma lipid profiles. Cluster 6 had significantly lower levels of plasma βGlcCers and a higher frequency of cord blood plasmacytoid dendritic cells that mediate anti-inflammatory responses, which is consistent with an anti-inflammatory profile. For clusters and for each infant, a proinflammatory lipid index was calculated to reflect the sum of the proinflammatory lipids minus the anti-inflammatory lipids that were significantly different than in cluster 6. The cluster proinflammatory lipid index was associated with cord blood basophil frequency and with wheeze and atopic dermatitis in the first year of life. The infant inflammatory lipid index was associated with increased risk of wheeze in the first year of life. Conclusion: The cord blood proinflammatory lipid index is associated with early-life atopic dermatitis and wheezing.
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    β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen
    (Frontiers Media, 2021-02) Walker, Matthew T.; Ferrie, Ryan P.; Hoji, Aki; Schroeder-Carter, Lindsay M.; Cohen, Jacob D.; Schnaar, Ronald L.; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    In animals and humans, offspring of allergic mothers have increased responsiveness to allergen and the allergen-specificity of the offspring can be different than that of the mother. In our preclinical models, the mother's allergic responses influence development of the fetus and offspring by elevating numbers of cells in dendritic cell subsets. A major question is the identity of maternal factors of allergic mothers that alter offspring development of responsiveness to allergen. Lipids are altered during allergic responses and lipids are transported to the fetus for growth and formation of fetal membranes. We hypothesized that pro-inflammatory lipids, that are elevated in allergic mothers, are transported to the fetus and regulate fetal immune development. We demonstrate in this report that there was a significant 2-fold increase in β-glucosylceramides (βGlcCer) in allergic mothers, the fetal liver and her offspring. The βGlcCer were transported from mother's plasma, across the placenta, to the fetus and in breastmilk to the offspring. Administration of βGlcCer to non-allergic mothers was sufficient for offspring responses to allergen. Importantly, maternal administration of a clinically relevant pharmacological inhibitor of βGlcCer synthase returned βGlcCer to normal levels in the allergic mothers and her offspring and blocked the offspring increase in dendritic cell subsets and offspring allergen responsiveness. In summary, allergic mothers had increased βGlcCer that was transported to offspring and mediated increases in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms for development of allergies in offspring of allergic mothers and have the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.
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    β-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells
    (American Association of Immunologists, 2022) Lajiness, Jacquelyn D.; Amarsaikhan, Nansalmaa; Tat, Kiet; Tsoggerel, Angar; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    In humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. The elevated βGlcCers increase numbers of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers increased development of GM-CSF-stimulated mouse bone marrow-derived DCs (BMDCs) in vitro without altering expression of costimulatory molecules. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCers increased PKCα and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Antigen processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. Pups of allergic mothers had an increased proportion of CD11b+CD11c+ subsets of DCs, contributing to enhanced stimulation of T cell proliferation ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for the prevention or intervention in asthma and allergic disease.