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* Laboratory of Electron Microscopy, National Institute for Infectious Diseases Istituto Nazionale per le Malattie Infettive "L. Spallanzani," Rome, Italy;
Department of Biology, University of Rome "Tor Vergata," Rome, Italy;
Department of Cellular and Developmental Biology, University of Rome "La Sapienza," Rome, Italy; and
Medical Research Council, Toxicology Unit, Leicester University, Leicester, United Kingdom
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-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The work was partially supported by grants from Ricerca Corrente e Finalizzata del "Ministero della Salute," Associazione Italiana per la Ricerca sul Cancro, and Telethon. L.T. is supported by "Fondazione Andrea Cesalpino," Policlinico Umberto I, Sapienza University of Rome.
2 Address correspondence and reprint requests to Dr. Mauro Piacentini, Department of Biology, University of Rome "Tor Vergata," Via della Ricerca Scientifica 1, 00133 Rome, Italy. E-mail address: mauro.piacentini{at}uniroma2.it
3 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; ChIP, chromatin immunoprecipitation; MPO, myeloperoxidase; SSC, side scatter; sTNFRI, soluble TNFRI; TG2, type II transglutaminase; WT, wild type.
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  S. E. Iismaa, B. M. Mearns, L. Lorand, and R. M. Graham Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders Physiol Rev, July 1, 2009; 89(3): 991 - 1023. [Abstract] [Full Text] [PDF]
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