Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells
- Zsuzsa Szondya,b,c,
- Zsolt Saranga,b,
- Péter Molnárd,
- Tamás Némethd,
- Mauro Piacentinie,
- Pier Giorgio Mastroberardinof,
- Laura Falascae,
- Daniel Aeschlimanng,
- Judit Kovácsd,
- Ildikó Kissa,
- Éva Szegezdia,
- Gabriella Lakosh,
- Éva Rajnavölgyii,
- Paul J. Birckbichlerj,
- Gerry Melinok,l, and
- László Fésüsa
- aDepartment of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, dDepartment of Pathology, hThird Department of Medicine, iInstitute of Immunology, University of Debrecen, Debrecen H-4012, Hungary; eNational Institute of Infectious Diseases “La Spallanzani,” 00149 Rome, Italy; Departments of fBiology and kExperimental and Biochemical Science, University of Tor Vergata, 00133 Rome, Italy; gMatrix Biology and Tissue Repair Research Unit, Dental School, University of Wales College of Medicine, Cardiff CF14 4XY, Wales, United Kingdom; jDepartment of Chemistry, Slippery Rock University, Slippery Rock, PA 16057; and lMedical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester LE1 9HN, United Kingdom
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Communicated by Laszlo Lorand, Northwestern University Medical School, Chicago, IL, April 25, 2003 (received for review February 20, 2002)
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.
