Transglutaminase type II is involved in the pathogenesis of endotoxic shock.
The pathogenesis of sepsis is characterized by the inability of the host to regulate the inflammatory response, and as a consequence, dysregulated inflammatory processes induce organ dysfunctions and death. Altered transglutaminase type II (TG2) expression is associated with the development of many inflammatory diseases. Therefore, in this study, we questioned whether TG2 could also contribute to the pathological inflammatory dysregulation occurring in septic shock in vivo. To this aim, we used as an experimental model the TG2 knockout mice, in which the process of septic shock was elicited by treatment with LPS. Interestingly, our results demonstrated that TG2 ablation leads to partial resistance to experimental sepsis. The increased survival of TG2(-/-) mice was reflected in a drastic reduction of organ injury, highlighted by a limited infiltration of neutrophils in kidney and peritoneum and by a better homeostasis of the proinflammatory mediators as well as mitochondrial function. We also showed that in wild-type mice, the TG2 expression is increased during endotoxemia and, being directly involved in the mechanisms of NF-kappaB activation, it may cause a continuous activation cycle in the inflammatory process, thus contributing to development of sepsis pathogenesis. We propose that the inhibition of TG2 could represent a novel approach in the treatment of inflammatory processes associated with sepsis.
Falasca
Laura
L
Laboratory of Electron Microscopy, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy.
Farrace
Maria Grazia
MG
Rinaldi
Alessandra
A
Tuosto
Loretta
L
Melino
Gennard
G
Piacentini
Mauro
M
D058186:Acute Kidney Injury / Q000201:enzymology / Q000473:pathology; D000818:Animals; D019446:Endotoxemia / Q000201:enzymology / Q000209:etiology / Q000401:mortality / Q000473:pathology; D004927:Escherichia coli Infections / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012772:Shock, Septic / Q000201:enzymology* / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D011503:Transglutaminases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins