Inhibition of transglutaminase 2 alleviates the dysregulated inflammatory response in sepsis-induced liver injury

Sepsis is the leading cause of lethal organ malfunction in hospitalized patients, which is characterized by a dysregulated inflammatory response to infection and multiple organ failure. Transglutaminase 2 (TG2) is a multifunctional enzyme with both pathogenic and protective roles in liver diseases. Here, we explored the role of TG2 in the pathogenic inflammatory dysregulation in sepsis mice. Administration of a TG2 inhibitor cystamine reduced liver injury and improved the survival rate of lipopolysaccharide (LPS) induced sepsis mice in a time-dependent manner. Profiling of inflammatory cytokines showed that interferon-γ (IFNγ) expression was suppressed in the liver, lung and kidney of mice administrated with cystamine or in TG2 knockout mice. Then, an ex vivo imaging approach was established to examine the in vivo transamidase activity of TG2 based on the intraperitoneal injection of 5-biotinamidopentylamine (5BAPA), a biotinylated substrate for TG2. 5BAPA signals were increased in the livers of LPS and cecal ligation and puncture-induced sepsis mice, especially in F4/80-positive midzonal macrophages. These phenomena were prevented by administration with cystamine or in the livers of TG2 knockout mice. Finally, in vitro macrophage depletion with clodronate liposomes dramatically decreased the inflammatory response to LPS, especially IFNγ gene expression. In summary, TG2 alleviates liver injury partly through regulating the dysregulated inflammation in macrophage, which may represent a potential marker and therapeutic target in sepsis.