Deubiquitinase USP7 Regulates Neutrophil Extracellular Trap Formation and Inflammation in Lipopolysaccharide-Treated Mice Through ICAM-1 Expression.

Abstract

Sepsis is typified by organ failure due to an unchecked host reaction to infection. This study aims to explore the mechanism of ubiquitin-specific peptidase 7 (USP7) in sepsis with the involvement of intercellular adhesion molecule-1 (ICAM-1). A sepsis model was established using lipopolysaccharide (LPS) induction in WT and USP7mice, and various assays were conducted to evaluate survival rates, organ damage, inflammatory markers, and protein interactions. The results revealed that USP7 expression increased in LPS-treated WT mice, and its interaction with ICAM-1 stabilized ICAM-1 through deubiquitination. USP7 knockout significantly elevated survival rates of septic mice. USP7 knockout reduced pulmonary inflammation, neutrophil extracellular trap (NET) formation, and myeloperoxidase and Cit-H3 levels in septic mice. Moreover, USP7 knockout lowered the levels of organ injury markers (creatine kinase-MB [CK-MB], troponin-I, and blood urea nitrogen [BUN]), liver enzymes (ALT and AST), and inflammatory markers (TNF-α, IL-1β, IL-6, and IL-8). Co-culture of bone marrow-derived macrophages (BMDMs) from WT mice with ICAM-1+ neutrophils elevated levels of TNF-α, IL-1β, and IL-6. These findings suggest that USP7 plays a critical role in driving sepsis-induced NET formation and inflammation by stabilizing ICAM-1. Targeting USP7 may represent a potential therapeutic approach to mitigate sepsis-related inflammation and organ damage.