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Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells

Szondy, Zsuzsa, Sarang, Szolt, Molnar, Peter, Nemeth, Tamar, Piacentini, Mauro, Mastroberardino, Pier Giorgio, Falasca, Laura, Aeschlimann, Daniel, Kovacs, Judit, Kiss, Ildico, Szegezdi, Eva, Lakos, Gabriella, Rajnavolgyi, Eva, Birckbichler, Paul J., Melino, Gerry and Fesus, Laszlo 2003. Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proceedings of the National Academy of Sciences 100 (13) , pp. 7812-7817. 10.1073/pnas.0832466100

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Abstract

Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2-/- mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or γ-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-β1 in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4+CD8+ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2-/- mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process. Transglutaminases (TGases) (1) are a family of thiol- and Ca2+-dependent acyl transferases that catalyze the formation of a covalent bond between the γ-carboxamide groups of peptide-bound glutamine residues and various primary amines, including the ε-amino group of lysine in certain proteins. The reaction results in posttranslational modification of proteins by establishing ε-(γ-glutamyl)lysine crosslinkages and/or covalent incorporation of polyamines and histamine into proteins. Eight distinct enzymatically active transglutaminases have so far been described (1, 2). One of them, TGase2, has additionally G protein signaling activity (3). TGase2 is ubiquitously expressed in mammalian tissues (4) found both extracellularly at the cell surface in association with the extracellular matrix (5) and intracellularly in membrane-associated as well as cytosolic form. TGase2 has been implicated in a variety of cellular processes, including signaling (6), signal transduction (3), cell adhesion and spreading (7), wound healing (8), and tissue mineralization (9). Additionally, it has also been demonstrated that TGase2 is one of the few genes induced during the in vivo apoptotic program (10–12). Cells expressing TGase2 antisense RNA are less sensitive to apoptosis induced by various agents, whereas cells overexpressing TGase2 have increased sensitivity (13, 14). Because intracellularly GTP, Zn2+,and nitric oxide inhibit the crosslinking activity of TGase2, the accumulation of TGase2 inside the cell is not necessarily associated with the activation of its crosslinking activity (15). However, Ca2+-dependent activation of the enzyme leads to the formation of a detergentinsoluble crosslinked protein scaffold in cells undergoing programmed cell death (16). This insoluble protein scaffold may stabilize the integrity of the dying cells before their clearance by phagocytosis, thus preventing the nonspecific release of harmful intracellular components and consequently inflammatory responses and scar formation in bystander tissues (17). Although TGase2 seems to be strongly linked to the in vivo apoptosis program (10–12), the up-regulation of TGase2 cannot be detected during the induction of in vitro apoptosis in many cells, suggesting that factors present only in the tissue environment are required for its induction in vivo (12). To assess the role of TGase2 in programmed cell death, TGase2-/- mice have been generated (18). Because these mice did not show an overt apoptosis-related phenotype during fetal life, we decided to investigate the role of TGase2 in the in vivo apoptosis program in distinct biological contexts by using the thymus and liver as model systems. Data presented in this study indicate that the lack of TGase2 affects both the killing and the clearance of dying cells. The disturbance of these events results from a deficiency in transforming growth factor (TGF)-β activation and is associated with the development of splenomegaly, autoantibodies, and glomerulonephritis in TGase2-/- mice. These findings have implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Publisher: National Academy of Sciences
ISSN: 10916490
Last Modified: 04 Jun 2017 01:35
URI: http://orca.cf.ac.uk/id/eprint/718

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