Bone marrow mesenchymal stem cell-derived exosomal miR-181a-5p promotes M2 macrophage polarization to alleviate acute pancreatitis through ZEB2-mediated RACK1 ubiquitination

Abstract

As a common digestive disease, acute pancreatitis (AP) often threatens the life of patients. Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have exhibited some benefits for AP. However, the mechanism remains unclear and deserves to be further investigated. The characteristics of BMSCs-exosomes (BMSCs-Exos) were identified. The abundance of genes and proteins was evaluated using quantitative real-time PCR (RT-qPCR), western blot, enzyme-linked immunosorbent assay (ELISA) and IF assay. Cell apoptosis and CD206-positive cells were measured by flow cytometry. The interactions among miR-181a-5p, Zinc finger E-box binding homeobox 2 (ZEB2) and Receptor for Activated C Kinase 1 (RACK1) were verified using dual luciferase reporter assay, RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP). BMSCs-Exos effectively improved AP injury through restraining AR42J cell apoptosis and promoting M2 macrophage polarization, which was realized due to BMSCs-Exos harboring an abundance of miR-181a-5p. Further experiments validated miR-181a-5p silenced ZEB2 and ZEB2 reduced RACK1 expression through mediating RACK1 ubiquitination. ZEB2 knockdown decreased AR42J cell apoptosis and induced M2 macrophage polarization to alleviate AP injury, whereas RACK1 downregulation abolished these phenomena. BMSCs-Exos harboring miR-181a-5p suppressed AR42J cell apoptosis and promoted M2 macrophage polarization to delay AP progression through ZEB2-mediated RACK1 ubiquitination.