Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα‐dependent inflammation and apoptosis. Issue 3 (10th February 2021)

• Record Type: Journal Article
• Authors: Avni, Dorit; Harikumar, Kuzhuvelil B.; Sanyal, Arun J.; Spiegel, Sarah
• Is Part Of: FASEB journal. Volume 35:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-02-10
• Subjects: acute liver failure -- apoptosis -- cytokines -- sphingosine kinase; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202002540R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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‐κB 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 TNFα. 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 TNFα 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 TNFα 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.