| First Author | Avni D | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 3 | Pages | e21415 |
| PubMed ID | 33566377 | Mgi Jnum | J:320695 |
| Mgi Id | MGI:6741351 | Doi | 10.1096/fj.202002540R |
| Citation | Avni D, et al. (2021) Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFalpha-dependent inflammation and apoptosis. FASEB J 35(3):e21415 |
| abstractText | 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-kappaB 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 TNFalpha. 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 TNFalpha 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 TNFalpha 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. |
