Downregulated PLAU alleviates acute rejection after liver transplantation by targeting Ptgs2 in macrophages

Background Acute rejection (AR) is a major determinant of poor prognosis after liver transplantation (LT), and macrophage M1-polarization can induce AR. Urokinase-type plasminogen activator (PLAU) has been implicated in the regulation of several liver diseases, but its role in AR remains unclear. Methods In this study, through bioinformatics analysis and transcriptome sequencing, we find that PLAU and prostaglandin-endoperoxide synthase 2 (Ptgs2) can regulate macrophage polarization. To elucidate the effects of PLAU and Ptgs2 on AR, dynamic changes in PLAU and Ptgs2 expression are detected in both peripheral blood mononuclear cells (PBMCs) from clinical LT patients and hepatic macrophages from LT rats. Subsequently, to investigate the specific regulatory roles in macrophage M1-polarization and AR, downregulating PLAU and Ptgs2 rescue experiments are conducted in vivo and in vitro . Finally, potential signaling pathways are further identified through KEGG enrichment analysis. Results The expression of PLAU and Ptgs2 is increased in PBMCs from LT patients and in macrophages from LT rats, and most significantly on postoperative day 7. Downregulating PLAU alleviates AR and suppresses M1-polarization of macrophages. However, Ptgs2 rescue exacerbates AR and promotes M1-polarization of macrophages. The potential mechanism involves regulating the Protein kinase B/Nuclear factor kappa B (AKT/NF-κB) pathway. Conclusion In summary, downregulated the PLAU/Ptgs2 axis can attenuate AR by regulating macrophage polarization, offering a promising new therapeutic target for preventing and treating AR.