Phospholipid phosphatase 6 (PLPP6) regulates polyisoprenoid diphosphate signaling in cell activation. In response to pro-inflammatory stimuli, PLPP6 converts presqualene diphosphate (PSDP) into its monophosphate form (PSMP). Because polyisoprenoids serves fundamental roles in cell immunology, we generated mice deficient in Plpp6 (Plpp6 -/-) to investigate its role in isoprenoid remodeling and cellular responses in vivo. Naïve Plpp6-/- had lower total and cellular cholesterol levels. In house dust mite (HDM)-induced lung allergic inflammation, Plpp6-/- mice had reduced conversion of PSDP into PSMP. Plpp6-/- mice had lower numbers of lung eosinophils, neutrophils and dendritic cells (DCs) relative to WT. In addition, Plpp6-/- mice also had lower expression of type 2 cytokines and serum IgE levels. Uptake of labeled HDM by DCs in vivo was decreased in Plpp6-/- mice, and in vitro Plpp6-/- DCs uptake of labeled dextran by macropinocytosis was decreased with lower phosphoinositide 3-kinase (PI3K) expression and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) formation compared to WT. Together, these results indicate that PLPP6 deficiency leads to lower cellular cholesterol levels, reduced polyisoprenoid diphosphate remodeling, decreased DC macropinocytosis and reduced allergen-driven tissue inflammation, and suggest a pivotal role for PLPP6 in mediating allergic responses to environmental stimuli.
Thayse Bruggemann– PhD, Brigham and Women's Hospital and Harvard Medical School
Nandini Krishnamoorthy– Brigham and Women's Hospital and Harvard Medical School
Melody Duvall– Brigham and Women's Hospital and Harvard Medical School
Raja-Elie Abdulnour– Brigham and Women's Hospital and Harvard Medical School
Bruce Levy– Brigham and Women's Hospital and Harvard Medical School