Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα-dependent inflammation and apoptosis

Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi-organ failure and death. Previous studies suggest that sphingosine kinase 1 (SphK1) protects against hepatocyte injury, yet not much is still known about its involvement in ALF. This study examines the role of SphK1 in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF, which is a well-established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN/LPS-induced liver damage, hepatic apoptosis, serum alanine aminotransferase levels, and mortality rate compared to wild-type mice. Whereas GalN/LPS treatment-induced hepatic activation of NF-kappa B and JNK in wild-type and SphK2(-/-) mice, these signaling pathways were reduced in SphK1(-/-) mice. Moreover, repression of ALF in SphK1(-/-) mice correlated with decreased expression of the pro-inflammatory cytokine TNF alpha. Adoptive transfer experiments indicated that SphK1 in bone marrow-derived infiltrating immune cells but not in host liver-resident cells, contribute to the development of ALF. Interestingly, LPS-induced TNF alpha production was drastically suppressed in SphK1-deleted macrophages, whereas IL-10 expression was markedly enhanced, suggesting a switch to the anti-inflammatory phenotype. Finally, treatment with a specific SphK1 inhibitor ameliorated inflammation and protected mice from ALF. Our findings suggest that SphK1 regulates TNF alpha secretion from macrophages and inhibition or deletion of SphK1 mitigated ALF. Thus, a potent inhibitor of SphK1 could potentially be a therapeutic agent for fulminant hepatitis.