スフィンウレタンキナーゼ1はマクロファージの募集と分極を介して肝線維化を促進する

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

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<p>Macrophage recruitment and polarization play pivotal roles in the initiation and progression of liver fibrosis. Our previous study has demonstrated that Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs) in liver fibrosis. However, the role of SphK1 in hepatic macrophage recruitment and polarization remains unclear. In this study, Single-cell transcriptomics illustrated that SphK1 is highly expressed in monocytes/macrophages and upregulated during both stages of macrophage M1 and M2 polarization. Consistently, SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrotic livers. SphK1 deletion reduced the recruitment of hepatic macrophages and inhibited M1 and M2 polarization in CCl4-induced mice. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via CCL2. SphK1 in macrophage activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier (SUMO) specific peptidase1 (SENP1) so as to decrease de-SUMOylation of Kruppel-like factor 4 (KLF4) to promote M2 polarization. Together, our findings highlighting that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and polarization and might serve as a potential drug target for the treatment of liver fibrosis.</p>

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