Abstract
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.
Highlights
The prevalence of allergic diseases and asthma have dramatically increased in the last 40 years [1,2,3]
These data indicate that maternal sphingosine 1-phosphates (S1P) in allergic mothers is metabolized to sphingosine in the placenta and that S1P is not elevated in the fetal liver
We demonstrated that in allergic mothers, increased maternal βGlcCer is necessary and sufficient to increase offspring lung eosinophilia in response to allergen
Summary
The prevalence of allergic diseases and asthma have dramatically increased in the last 40 years [1,2,3]. The offspring of Maternal β-Glucosylceramide Increases Offspring Allergy allergic mothers, that do not receive an allergen challenge, do not have lung eosinophilia and do not have airway hyperresponsiveness, indicating that pup lung responses are induced by allergen challenge of the offspring of allergic mothers [5]. In mice, transfer of dendritic cells (DCs) from neonates of allergic mothers (but not macrophages) to recipient neonates from non-allergic mothers transfers the enhanced allergic responsiveness to the recipient neonates [4, 12] This indicates that DCs of offspring of allergic mothers are sufficient for the allergen responsiveness. We have shown that the fetal liver and offspring of these allergic mothers have increased numbers of distinct subsets of CD11b+ CD11c+ DCs without altering CD103+ DCs [13, 14]. These lung DCs of OVA-challenged pups of allergic mothers are of a Th2 phenotype as demonstrated by increased numbers of IRF+ DCs [14]
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