<i>Pseudomonas aeruginosa</i> stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury.

Abstract

Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression. Profile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with <i>Pseudomonas aeruginosa</i> (<i>PA</i>) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by <i>PA</i> using genetically engineered mice was determined. Genetic deletion of <i>Sphk2</i>, but not <i>Sphk1</i>, in mice conferred protection from <i>PA</i>-mediated lung inflammation. <i>PA</i> infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced <i>PA</i>-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF). Our studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.