Nuclear SphK2 and S1P Signaling Epigenetically Regulates Pseudomonas aeruginosa Induced Lung Inflammation
Ebenezer, David L
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Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of human diseases such as pulmonary disorders such as pulmonary fibrosis, asthma, sepsis and pulmonary hypertension. Here we identified nuclear activation of sphingosine kinase (SphK) 2 and generation of sphingosine 1-phosphate (S1P) in Pseudomonas aeruginosa (PA) infected lung epithelial cells and determined its role in upregulation of the secretion of pro-inflammatory cytokines in the epithelium. Genetic deletion of SphK2, but not SphK1, in mice conferred protection from PA-mediated lung inflammatory injury. PA infection stimulated phosphorylation of SphK2 and its localization in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SphK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, IL-6 and TNF-α. Further, PA infection of the epithelial cells enhanced NOX4 dependent nuclear reactive oxygen species (ROS) production and oxidation of histone deacetylase (HDAC) 1 & 2, which was dependent on PKC δ and SphK2 activation and was blocked by N-acetylcysteine. The clinical significance of our findings is supported by nuclear localization of p-SphK2 in alveolar and bronchial epithelial cells of lung specimens from CF patients chronically infected with PA. Thus, our studies define a critical role for nuclear SphK2/S1P signaling in epigenetic regulation of inflammatory lung injury by bacterial infection.
SubjectSphingosine Kinase 2, Epigenetics