Mesenchymal stem cells-derived TGF-β1 promotes polarization of M2 macrophages in mice with acute-on-chronic liver failure via FOSL1/MERTK axis.

BACKGROUND & AIMS: Macrophages related inflammation plays a pivotal role in the progression of acute-on-chronic liver failure (ACLF). Our previous study has found that mesenchymal stem cells (MSCs) alleviate inflammatory damage in ACLF mice by promoting polarization of M2 macrophages through upregulating the expression of Mer tyrosine kinase (MERTK). In this study, we investigate the specific mechanism by which MSCs regulate MERTK. METHODS: Bioinformatics was used to predicted the candidate transcription factors for Mertk gene and FOS like antigen 1(FOSL1) was chosen. After overexpressing or knocking down Fosl1, MERTK, iNOS and Arg-1 were analyzed in Raw264.7 and/or J774a.1 cells. Conditioned medium (CM) of MSCs was cocultured with macrophages and the expressions of TGF-β1 and FOSL1 were detected. Male Balb/c mice aged 5-6 weeks were used to establish ACLF mice model. And adeno-associated virus or MSCs-CM was injected through tail vein. Then mouse liver tissue was collected and analyzed. RESULTS: FOSL1 promotes M2 polarization of macrophages by upregulating the expression of MERTK in vivo and in vitro. The luciferase reporter assays indicate that FOSL1 acts as a transcription factor of Mertk gene. Furthermore, MSCs-CM promotes expression of FOSL1 and M2 polarization of macrophages through TGF-β1 receptor. After knocking down TGF-β1 in MSCs using shRNA, shRNA-CM could not upregulate the expression of FOSL1, and promote M2 polarization of macrophages as CM does. CONCLUSIONS: Our findings show that TGF-β1 secreted by MSCs promotes M2 macrophages polarization via FOSL1/MERTK axis in ACLF mice, providing a novel therapeutic target for ACLF treatment.