β-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells

Abstract

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. 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 (C16:0, C18:0, C18:1, and C24:1) increased development of GM-CSF-stimulated bone marrow-derived DCs (BMDCs) in vitro. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCer 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. However, lung DCs from pups of allergic mothers had an increased proportion of CD11b+CD11c+ DCs and exhibited enhanced stimulation of T cells 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 approaches in the prevention or intervention in asthma and allergic disease. Supported by grants from the NIH (U01 AI131337 (Cook-Mills), R01AI127695 (Cook-Mills)) as well as the Pediatric Scientist Development Program (Lajiness) and Marshall Klaus Perinatal Research Award (Lajiness)