Importance of Selenoprotein O in Regulating Hmgb1: A New Direction for Modulating ROS-Dependent NETs Formation to Aggravate the Progression of Acute Liver Inflammation

Selenoproteins (Sels) are a class of essential biomolecules that play critical roles in cellular homeostasis. <i>SelO</i> was identified as the preferential source of selenium in the liver, implying its potential as a key regulatory factor in hepatic pathophysiology. Bioinformatics analysis of data from GEO data sets revealed marked downregulation of <i>SelO</i> in liver injury. However, its function and regulatory mechanisms in the liver remain unclear. To address this, we investigated the effect of <i>SelO</i> ablation on acute liver inflammation, focusing on its association with inflammation and neutrophil extracellular traps (NETs) formation. Wild-type (WT) and <i>SelO</i>-knockout mice were used to establish a lipopolysaccharide (LPS) exposure model and a coculture model (AML12 cells and neutrophils) in vitro. Our findings revealed that LPS stimulation significantly reduced <i>SelO</i> expression in the WT mouse liver. <i>SelO</i> deletion promoted the expression of <i>Hmgb1</i> and marker cytokines for chemokines, NETs generation, pyroptosis and inflammation, and induced an imbalance in redox homeostasis. Immunofluorescence, SYTOX staining, and scanning electron microscopy confirmed that <i>SelO</i> silencing promoted reactive oxygen species (ROS)-dependent NETs formation. Moreover, the coculture model demonstrated that excessive NETs formation exacerbated <i>SelO</i>-ablation-induced hepatic inflammation. Importantly, we confirmed the significant involvement of the Hmgb1/ROS axis in the development of acute liver inflammation in the absence of <i>SelO</i>. Our results demonstrated that <i>SelO</i> ablation promoted neutrophil recruitment and enhanced ROS-dependent NETs formation by increasing <i>Hmgb1</i> expression levels, thereby aggravating LPS-induced pyroptosis and inflammation. This study not only uncovered the crucial biological functions of <i>SelO</i>, but also shed light on its regulatory implications in the inflammatory process.