Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization.

Abstract

Background & aims: Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis.

Methods: Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1^-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation. The direct effects of SphK1 on macrophage polarization were also investigated in vitro. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples.

Results: SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by carbon tetrachloride. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via C-C motif chemokine ligand 2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier-specific peptidase1 to decrease de-SUMOylation of Kruppel-like factor 4 to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers.

Conclusions: Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.