Sphingosine kinase 1 promotes liver fibrosis by preventing miR‐19b‐3p‐mediated inhibition of CCR2

Abstract

Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1‐dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human. SphK1 was coexpressed with a range of HSC/KC markers including desmin, α‐smooth muscle actin (α‐SMA) and F4/80 in fibrotic liver. Deficiency of SphK1 (SphK1−/−) resulted in a marked amelioration of hepatic injury, including transaminase activities, histology, collagen deposition, α‐SMA and inflammation, in CCl4 or bile duct ligation (BDL)‐induced mice. Likewise, treatment with a specific inhibitor of SphK1, 5C, also significantly prevented liver injury and fibrosis in mice induced by CCl4 or BDL. In cellular levels, inhibition of SphK1 significantly blocked the activation and migration of HSCs and KCs. Moreover, SphK1 knockout in KCs reduced the secretion of CCL2, and SphK1 knockout in HSCs reduced C‐C motif chemokine receptor 2 ([CCR2] CCL2 receptor) expression in HSCs. CCL2 in SphK1−/− mice was lower whereas microRNA‐19b‐3p in SphK1−/− mice was higher compared with wild‐type (WT) mice. Furthermore, microRNA‐19b‐3p downregulated CCR2 in HSCs. The functional effect of SphK1 in HSCs on liver fibrosis was further strengthened by the results of animal experiments using a bone marrow transplantation (BMT) method. Conclusion: SphK1 has distinct roles in the activation of KCs and HSCs in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR‐19b‐3p. (Hepatology 2018).

M2b macrophage polarization and its roles in diseases

“…Sphingosine kinases (two isoforms, SPHK1 and SPHK2) catalyze the formation of sphingosine 1‐phosphate (S1P), a lipid mediator that functions in mammalian cells as an intracellular second messenger, as well as a ligand for S1P‐specific G‐protein‐coupled receptors . SPHK1 can be expressed in many types of cells, including monocytes, macrophages, hepatic stellate cells, and smooth muscle cells . Previous studies have shown that SPHK1 is mainly expressed in M2b and suggested that it can be used as a marker for M2b monocytes/macrophages .…”

“…64 SPHK1 can be expressed in many types of cells, including monocytes, macrophages, hepatic stellate cells, and smooth muscle cells. 34,[65][66][67][68] Previous studies have shown that SPHK1 is mainly expressed in M2b and suggested that it can be used as a marker for M2b monocytes/macrophages. 1,34,47,48 However, Mantovani and his colleagues reported that SPHK1 is expressed at higher levels in M1 than M2 cells.…”

“…69 In addition, some researchers have found that SPHK1 is expressed in M2c. 6,70,71 The expression of SPHK1 is not restricted to M2b macrophages 66,67,69 ; thus, it should not be used as a sole marker to identify M2b macrophages.…”

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

“…Liver fibrosis is a wound‐healing response to chronic liver injury . During chronic injury, the liver parenchyma is gradually replaced with excessive extracellular matrix, eventually causing disruption of liver architecture and the loss of liver function.…”

iRhom2 serves as a facilitator in obesity by enhancing adipose inflammation and insulin resistance

“…The above data have extruded the role of iRhom2 in HFD-induced adipose inflammation and macrophages activation. In view of such situation, we attempted to deeply explore the role for iRhom2 in macrophages in adipose inflammation using bone marrow transplantation (BMT), a method that has been widely used for changing gene expression of macrophages (26,27). The lethally irradiated WT mice were transplanted with bone marrow cells isolated from iRhom2 KO mice and/or WT mice to generate a KOBM→WT mice.…”