Sphingosine 1-Phosphate Receptor 2 and 3 Mediate Bone Marrow-Derived Monocyte/Macrophage Motility in Cholestatic Liver Injury in Mice

Abstract

Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) system has been implicated in the pathological process of liver injury. This study was designed to evaluate the effects of S1P/S1PR on bone marrow-derived monocyte/macrophage (BMM) migration in mouse models of cholestatic liver injury, and identify the signaling pathway underlying this process. S1PR1–3 expression in BMM was characterized by immunofluorescence, RT-PCR and Western blot. Cell migration was determined in Boyden chambers. In vivo, the chimera mice, which received BM transplants from EGFP-transgenic mice, received an operation of bile duct ligation (BDL) to induce liver injury with the administration of S1PR2/3 antagonists. The results showed that S1PR1–3 were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR2 and S1PR3. Furthermore, PTX and LY-294002 (PI3K inhibitor) prevented S1PR2/3-mediated BMM migration, and Rac1 activation by S1P was inhibited by JTE-013, CAY-10444 or LY294002. Administration of S1PR2/3 antagonists in vivo significantly reduced BMM recruitment in BDL-treated mice, and attenuated hepatic inflammation and fibrosis. In conclusion, S1P/S1PR2/3 system mediates BMM motility by PTX-PI3K-Rac1 signaling pathway, which provides new compelling information on the role of S1P/S1PR in liver injury and opens new perspectives for the pharmacological treatment of hepatic fibrosis.

Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway

“…However, although BMMs are known to have unique characteristics, the roles of S1P signaling in the regulation of macrophage polarization during liver injured are poorly understood. Our preceding study has showed that blockade of S1PR 2/3 decreased liver inflammation and fibrosis by preventing BMM migration [20]. In the current study, we thus investigated the effects of S1P on BMM further, focusing on BMM polarization.…”

“…Our previous studies have shown that recruitment of BMMs in the injured liver could aggravate liver inflammation and thus played a crucial role in BDL-or CCl 4 -induced liver disease [20,29,30]. Among a variety of factors that mediate switch BMMs to pro-inflammatory M1 phenotype, S1P is probably one of the most potent regulatory molecules [36].…”

“…These S1PRs bind to distinct heterotrimeric G-proteins and regulate different signaling pathways [19]. Our previous studies have shown that S1P/S1PR 2/3 is involved in bile duct ligation (BDL)-or carbon tetrachloride (CCl 4 )-induced liver injury [20]. However, the role of S1P/S1PRs in functional polarization of macrophage remains incompletely defined.…”

“…Meanwhile, the analysis in vivo and in vitro suggested that bone marrow (BM)-derived monocytes/macrophages (BMMs) were recruited to the damaged liver [29,30] and exposed to high levels of S1P in the hepatic microenvironment. Furthermore, it was also found that BMMs presented a proinflammatory property during the process [20]. Based on these previous in vivo and in vitro studies, we determined whether S1P is involved in the pro-inflammatory M1 polarization of BMMs, and identified the signaling pathway that mediates S1P-induced M1 polarization in BMMs.…”

Pathogenesis of Kupffer Cells in Cholestatic Liver Injury

“…48,49 A recent study has shown that sphingosine 1-phosphate receptor 2 and 3 mediate bone marrowederived monocyte recruitment in BDL mice. 50 These earlier findings suggest that not only Kupffer cells but also bone marrowederived macrophages may play key roles in liver repair…”