Common immunotoxicity mechanisms of hepatotoxicity induced by raw Polygonum multiflorum and Polygonum multiflorum praeparata: Inhibition of M2 macrophage polarization

Abstract

Macrophage polarization has been linked to hepatotoxicity induced by raw Polygonum multiflorum (RPM) and Polygonum multiflorum praeparata (PMP), but the regulatory mechanisms behind this remain unclear. This study aims to investigate the regulatory effects of RPM and PMP on M2 macrophages and the potential mechanisms. Sprague-Dawley rats were exposed to RPM and PMP under lipopolysaccharide (LPS) stimulation. RAW264.7 cells induced with IL-4 were treated with RPM and PMP. Under LPS stimulation, both RPM and PMP increased serum enzyme levels and pro-inflammatory factor levels and induced histopathological injury. M1 macrophage infiltration and M1 gene expression in the liver increased, whereas M2 macrophage infiltration and M2 gene expression decreased. RPM and PMP inhibited M2 gene expression and reduced green fluorescence intensity. RNA sequencing and metabolomics revealed that RPM regulated sphingolipid signaling and Janus kinase/signal transducer and activator of transcription signaling pathways, while PMP influenced arginine and proline metabolism, arginine biosynthesis, and cholesterol metabolism pathways. RPM and PMP orchestrate distinct signaling pathways, thereby inhibiting M2 macrophage polarization and inducing hepatotoxicity. This study not only elucidates the pathophysiology underlying RPM- and PMP-induced hepatotoxicity, but also provides insights for the development of new therapeutic interventions.