Nuclear S1P Lyase Regulates Histone Acetylation In Pseudomonas aeruginosa ‐Induced Lung Inflammation

Abstract

Sphingosine -1-Phosphate (S1P), a bioactive sphingolipid, regulates various cellular processes, including vascular integrity and inflammation. Sphingosine-1-Phosphate Lyase (S1PL), the enzyme that irreversibly degrades S1P to hexadecenal and phosphoethanolamine, regulates the intracellular levels of S1P and is also recognized to modulate inflammatory responses. Pseudomonas aeruginosa, a gram-negative opportunistic pathogen, is the common cause of pneumonia in ventilator-induced and immuno-compromised patients that is associated with increased morbidity and mortality. Understanding the role of sphingolipid metabolism in P. aeruginosa-induced lung inflammation is critical to improve clinical outcome of sepsis patients. Our study aims to define the epigenetic role of S1PL in modulating inflammatory responses in P. aeruginosa induced lung inflammation. Nuclei isolated from mouse lung epithelial cells (MLE-12) exhibited S1PL activity as determined by LC-MS/MS.Over-expression of S1PL resulted in elevated S1PL levels in both the cytosol and nucleus, and inhibition of S1PL by 4-deoxy pyridoxine elevated nuclear S1P levels. Also, blocking S1PL expression attenuated P. aeruginosa-induced Histone H3 and H4 acetylation. Interestingly, exogenous addition of Δ2-hexadecenal (1-100 nM) to isolated intact nuclei of MLE-12 cells induced Histone H3 and H4 acetylation, suggesting an epigenetic role of fatty aldehyde released from S1P by S1PL. Thus, targeting S1PL enzyme could be a novel mechanism for the treatment of bacterial infection of the lungs.