The role of sphingosine kinase in influenza virus mediated inflammasome activitation
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Influenza viruses continue to pose a grave burden on the global health and economy. Dysregulated innate immune system can lead to rapid infiltration of immune cells to the lungs followed by a cytokine storm, which contributes to immune mediated pathology and high morbidity and mortality. Importantly, IL-1[beta] produced via the activation of the NLRP3 inflammasome upon influenza virus infection is an important contributor of immunopathology. Sphingosine kinase (SK) modulates the level of sphingosine-1 phosphate (S1P), which is a key regulator of diverse physiological processes including inflammation. Here, we studied the role of SK in influenza virus-induced inflammasome activation. Pharmacologic inhibition of SK blocked the synthesis of IL-1[beta] upon influenza virus infection. This occurred in a dose-dependent manner, demonstrating the immunoregulatory function of SK. The SK inhibitor displayed its inhibitory activity at two separate stages. It suppressed TLR7-stimulated expression of pro-IL-1[beta] and impaired ATP-induced secretion of IL-1[beta] from dendritic cells (DCs) or macrophages. The production of IL-1[beta] was reduced in SK1-deficient DCs compared to wild type DCs. Thus, our data suggest that SK is a novel therapeutic target in alleviating influenza virus-induced immune pathology.
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