Maternal Lipids Regulate Neonatal Dendritic Cells During Development of Allergic Disease

Jacquelyn D. Lajiness, Indiana University School of Medicine, Indianapolis, IN, United States; Kiet Tat, Indiana University School of Medicine, United States; Joan Cook-Mills, Indiana University School of Medicine, IN, United States

Background: 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. The elevated maternal βGlcCers are both necessary and sufficient to increase numbers of offspring fetal liver CD11c+CD11b+ dendritic cells (DCs) and allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol (αT) and γ-tocopherol (γT). However, it is not known whether βGlcCers and tocopherols directly regulate development of DCs or which signaling pathways may be involved.

Objectives: We hypothesize that βGlcCers increase development of distinct subsets of CD11c+CD11b+ DCs via protein kinase C (PKC) activation.

Design/Methods: We treated mouse bone marrow cultures with βGlcCers and tocopherol isoforms during generation of DCs. DC phenotypes and intracellular signaling were analyzed by immunolabeling for CD45, CD11b, Ly6c, CD11c, MHCII, and phospho-Ser645-PKCδ and then analyzed by flow cytometry.

Results: In vitro treatment with βGlcCers increased numbers of CD11c+CD11b+ DC subsets including monocyte-derived DCs (mDCs) and resident phenotype DCs (rDCs). Treatment with γT alone similarly increased mDC and rDC while treatment with αT alone did not affect numbers of DCs. Interestingly, when co-administered with βGlcCers, αT mitigated the βGlcCer-induced increase in DC subsets while γT potentiated it. βGlcCers also increased PKCδ activation in mDCs and rDCs. This effect was blocked by αT. In contrast, γT independently increased PKCδ activation. Furthermore, administration of a PKCδ specific inhibitor was sufficient to block the βGlcCer-induced increase in mDCs and rDCs.

Conclusion: βGlcCers directly increased development of CD11c+CD11b+ DCs and PKC activation in bone marrow-derived DC cultures. This effect was modifiable by dietary tocopherols. These biological effects of βGlcCer and tocopherols on DCs are not currently well understood but our novel findings suggest that PKCδ plays a significantly role. This may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease.