• Anna Caretti, Alessandra Bragonzi, Marcella Facchini, Ida De Fino, Camilla Riva, Paolo Gasco, Claudia Musicanti, Josefina Casas, Gemma Fabriàs, Riccardo Ghidoni, and Paola Signorelli.
• Department of Health Sciences, University of Milan, San Paolo Hospital, Italy.
• Biochim. Biophys. Acta. 2014 Jan 1;1840(1):586-94.

BackgroundSphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects.MethodsThe therapeutic potential of myriocin, an inhibitor of the sphingolipid de novo synthesis rate limiting enzyme (Serine Palmitoyl Transferase, SPT),was investigated in CF cells and mice models.ResultsWe treated CF human respiratory epithelial cells with myriocin, This treatment resulted in reduced basal, as well as TNFα-stimulated, inflammation. In turn, TNFα induced an increase in SPT in these cells, linking de novo synthesis of ceramide to inflammation. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P. aeruginosa challenge, enabled a significant reduction of lung infection and reduced inflammation.ConclusionsThe presented data suggest that de novo ceramide synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection.General SignificanceMyriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.© 2013 Elsevier B.V. All rights reserved.

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