Neutropenia with Impaired Immune Response to Streptococcus pneumoniae in Ceramide Kinase-Deficient Mice

• DOI: 10.4049/jimmunol.180.5.3457
• Publication Date: 2014-04-18T23:16:52Z
• Authors: Christine Graf; Barbara Zemann; Philipp Rovina; Nicole Urtz; Andrea Schanzer; Roland Reuschel; Diana Mechtcheria...; Matthias Müller; Evelin Fischer; Claudia Reichel; Susanna Huber; Janet Dawson; Josef G Meingassner; Andreas Billich; Satoru Niwa; Rudolf Badegruber; Paul P Van Veldhoven; Bernd Kinzel; Thomas Baumruker; Frédéric Bornancin
• Keywords: Sphingolipid

In mammals, ceramide kinase (CerK)-mediated phosphorylation of is the only known pathway to ceramide-1-phosphate (C1P), a recently identified signaling sphingolipid metabolite. To help delineate roles CerK and C1P, we knocked out gene in BALB/c mice by homologous recombination. All vitro as well cell-based assays indicated that activity completely abolished Cerk-/- mice. Labeling with radioactive orthophosphate showed profound reduction levels de novo C1P formed macrophages. Consistently, mass spectrometry analysis revealed major contribution formation C16-C1P. However, significant residual animals indicate alternative routes exist. Furthermore, serum proapoptotic these were significantly increased while dihydroceramide biosynthetic precursor reduced. Previous literature pointed role or innate immune cell function. Using variety mechanistic disease models, primary cells, found macrophage- mast cell-dependent readouts are barely affected absence CerK. number neutrophils was strikingly reduced blood spleen animals. When tested model fulminant pneumonia, developed more severe disease, lending support defect neutrophil homeostasis following ablation. These results identify key regulator levels, important implications for immunity regulation.