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Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells
Zsuzsa Szondy1, Zsolt Sarang, Peter Molnar
1Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Institute of Immunology, University of Debrecen, Debrecen H-4012, Hungary. szondy@indi.dote.hu
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 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.
Insights
Tissue transglutaminase 2 (TGase2) deficiency impairs apoptotic cell clearance, leading to autoimmune issues. This highlights TGase2
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Tissue transglutaminase 2 (TGase2) is implicated in apoptosis.
- Efficient clearance of apoptotic cells is crucial for immune homeostasis.
Purpose of the Study:
- To investigate the role of TGase2 in apoptotic cell clearance and its implications for autoimmune diseases.
Main Methods:
- Apoptosis induction in TGase2 knockout (TGase2-/-) mice using various stimuli (dexamethasone, anti-CD3 antibody, gamma-irradiation).
- Assessment of apoptotic cell clearance in thymus and liver.
- Analysis of transforming growth factor-beta1 (TGF-β1) production in macrophages.
- Evaluation of autoimmune manifestations (splenomegaly, autoantibodies, glomerulonephritis).
Main Results:
- Apoptosis occurred in TGase2-/- mice, but apoptotic cell clearance was defective.
- TGase2 deficiency impaired TGF-β1 production in macrophages, hindering phagocytosis.
- TGase2-/- mice developed splenomegaly, autoantibodies, and immune complex glomerulonephritis.
Conclusions:
- TGase2 is essential for efficient clearance of apoptotic cells.
- Defective apoptotic cell clearance due to TGase2 deficiency promotes autoimmunity.
- Findings link TGase2 to inflammation, autoimmunity, and the apoptosis-phagocytosis interplay.
