Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells.
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 gamma-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-beta1 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.
Szondy
Zsuzsa
Z
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Institute of Immunology, University of Debrecen, Debrecen H-4012, Hungary. szondy@indi.dote.hu
Sarang
Zsolt
Z
Molnar
Peter
P
Nemeth
Tamas
T
Piacentini
Mauro
M
Mastroberardino
Pier Giorgio
PG
Falasca
Laura
L
Aeschlimann
Daniel
D
Kovacs
Judit
J
Kiss
Ildiko
I
Szegezdi
Eva
E
Lakos
Gabriella
G
Rajnavolgyi
Eva
E
Birckbichler
Paul J
PJ
Melino
Gerry
G
Fesus
Laszlo
L
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008089:Listeria monocytogenes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D010587:Phagocytosis; D016133:Polymerase Chain Reaction; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases / Q000235:genetics* / Q000502:physiology*; D015854:Up-Regulation
D001323:Autoantibodies; D007075:Immunoglobulin M; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins