Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis

Abstract

Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival. We have shown that the co-culture of Candida albicans and hepatocytes activates and induces the translocation of TG2 into the nucleus. In addition, the expression and activation of TG2 in liver macrophages was dramatically induced in the lipopolysaccharide-injected and cecal ligation puncture-operated mouse models of sepsis. Based on these findings and recently published research, we have reviewed the current understanding of the relationship between TG2 and sepsis. Following the genetic and pharmacological inhibition of TG2, we also assessed the evidence regarding the use of TG2 as a potential marker and therapeutic target in inflammation and sepsis.

Keywords: Elafin; antibacterial; antiviral; covalent crosslinking; inhibitor; sepsis; transglutaminase.

Figure 1

Transglutaminase 2 activity and function. Transamidation activity of transglutaminase 2 (TG2) is activated by Ca²⁺ and catalyzes the formation of an isopeptide bond. TG2 function is also regulated by guanosine triphosphate (GTP) binding. Ca2+-binding to TG2 regulates apoptosis, cell survival, cell adhesion, and matrix stabilization, while the binding of GDP to TG2 regulates signal transduction and receptor activation.

Figure 2

Trappin is responsible for antibacterial and antiviral activities. Trappin has a signal sequence for secretion (Pre), a TG substrate domain with a repeat sequence KGQDPV, and an inhibitory region that has a whey acidic protein (WAP) motif. Trappin is crosslinked to the extracellular matrix (ECM) by TG, whereby an inhibitory region is released into the extracellular space. The WAP motif exerts antibacterial and antiviral activities.

Figure 3

TG2 activity in the liver of septic mice. (A) Representative images from the cecal ligation and puncture (CLP) procedures. (B) TG2 activity in the liver of CLP-operated mice. Immunofluorescence staining with 4′,6-diamidino-2-phenylindole (DAPI) (blue) and 5-biotinamidopentylamine (5BAPA) (red) in frozen liver sections obtained from mice 48 h after sham or CLP operations. Scale bar: 50 μm. (C) TG2 activity in the liver of lipopolysaccharides (LPS)-injected mice. Immunofluorescence staining with DAPI (blue), TG2 (green), and 5BAPA (red) in frozen liver sections obtained from mice injected intraperitoneally with LPS in the presence and absence of CTM. Scale bar: 50 μm. (D) TG2 activity in the liver of LPS-injected TG2 knockout (KO) mice. Immunofluorescence staining of DAPI (blue), TG2 (green), and 5BAPA (red) in frozen liver sections obtained from mice injected intraperitoneally with 10 mg/kg LPS for 24 h. Scale bar: 50 μm. These images have been adapted from a previous study [22].