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

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 USP7-/- mice, 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.