EGCG Alleviates Lipopolysaccharide-Induced Septic Shock by Inhibiting NET-Mediated ROS Production by Regulating CXCL2 Expression.

Abstract

In septic shock, neutrophil extracellular traps (NETs)-mediated reactive oxygen species (ROS) drive inflammation and organ failure, with reducing excessive NETs emerging as a therapeutic strategy. This study aimed to investigate whether chemokine (C-X-C motif) ligand 2 (CXCL2), previously linked to NET formation in acute lung injury (ALI), serves as a target for septic shock and whether epigallocatechin-3-gallate (EGCG) exerts protective effects via CXCL2. Through bioinformatics analysis and RT-qPCR, CXCL2 was found highly expressed in serum from septic shock patients and lipopolysaccharide (LPS)-induced septic rats, correlating with increased NETs (MPO-DNA, dsDNA, and H3Cit) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). In vitro, knocking down CXCL2 in human neutrophils significantly inhibited phorbol myristate acetate (PMA)-induced NETs formation and ROS production. In septic rats, treatment with EGCG reduced the levels of CXCL2 in serum and bronchoalveolar lavage fluid (BALF), suppressed markers of NETs in serum, BALF, and lung tissue, and alleviated lung inflammation. In vitro, EGCG significantly inhibited PMA-induced NETs formation and ROS production. Mechanistically, EGCG inhibited NETs and ROS by downregulating CXCL2, with these effects reversed by the overexpression of CXCL2. These findings confirm that CXCL2 promotes NET-mediated ROS production in septic shock, and EGCG alleviates injury by targeting CXCL2, highlighting CXCL2 as a potential therapeutic target and EGCG as a promising agent for septic shock treatment.