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Dive into the research topics where Zsuzsa Szondy is active.

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Featured researches published by Zsuzsa Szondy.


Proceedings of the National Academy of Sciences of the United States of America | 2003

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

Zsuzsa Szondy; Zsolt Sarang; Peter Molnar; Tamás Németh; Mauro Piacentini; Pier G. Mastroberardino; Laura Falasca; Daniel Aeschlimann; Judit Kovács; Ildikó Kiss; Eva Szegezdi; Gabriella Lakos; Éva Rajnavölgyi; Paul J. Birckbichler; Gerry Melino; László Fésüs

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.


FEBS Letters | 2005

Transglutaminase 2 in the balance of cell death and survival

László Fésüs; Zsuzsa Szondy

Transglutaminase 2 (TG2), a multifunctional enzyme with Ca2+‐dependent protein crosslinking activity and GTP‐dependent G protein functions, is often upregulated in cells undergoing apoptosis. In cultured cells TG2 may exert both pro‐ and anti‐apoptotic effects depending upon the type of cell, the kind of death stimuli, the intracellular localization of the enzyme and the type of its activities switched on. The majority of data support the notion that transamidation by TG2 can both facilitate and inhibit apoptosis, while the GTP‐bound form of the enzyme generally protects cells against death. In vivo studies confirm the Janus face of TG2 in the initiation of the apoptotic program. In addition, they reveal a further role: the prevention of inflammation, tissue injury and autoimmunity once the apoptosis has already been initiated. This function of TG2 is partially achieved by being expressed and activated also in macrophages digesting apoptotic cells and mediating a crosstalk between dying and phagocytic cells.


Journal of Immunology | 2009

Transglutaminase 2 Is Needed for the Formation of an Efficient Phagocyte Portal in Macrophages Engulfing Apoptotic Cells

Beáta Tóth; Éva Garabuczi; Zsoly Sarang; György Vereb; György Vámosi; Daniel Aeschlimann; Bernadett Blaskó; Baliant Becsi; Ferenc Erdodi; Adam Lacy-Hulbert; Ailiang Zhang; Laura Falasca; Raymond B. Birge; Zoltán Balajthy; Gerry Melino; László Fésüs; Zsuzsa Szondy

Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin β3. We have previously shown that TG2−/− mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bound form promotes phagocytosis. Besides being a binding partner for integrin β3, a receptor known to mediate the uptake of apoptotic cells via activating Rac1, we also show that TG2 binds MFG-E8 (milk fat globulin EGF factor 8), a protein known to bridge integrin β3 to apoptotic cells. Finally, we report that in wild-type macrophages one or two engulfing portals are formed during phagocytosis of apoptotic cells that are characterized by accumulation of integrin β3 and Rac1. In the absence of TG2, integrin β3 cannot properly recognize the apoptotic cells, is not accumulated in the phagocytic cup, and its signaling is impaired. As a result, the formation of the engulfing portals, as well as the portals formed, is much less efficient. We propose that TG2 has a novel function to stabilize efficient phagocytic portals.


Gut | 2003

Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues

Ilma Rita Korponay-Szabó; Kaija Laurila; Zsuzsa Szondy; Tuula Halttunen; Zsuzsanna Szalai; Ingrid Dahlbom; I. Rantala; Judit Kovács; László Fésüs; Markku Mäki

Background: Autoantibodies against transglutaminase 2 (TG2) are thought to be responsible for the endomysial (EMA), reticulin (ARA), and jejunal antibody (JEA) tissue binding of serum samples from coeliac patients but the exclusive role of TG2 in these staining patterns has not yet been established. Aims: To evaluate whether antigens other than TG2 contribute to EMA/ARA/JEA reactions. Patients: Serum samples from 61 EMA/ARA/JEA positive untreated patients with coeliac disease, 40 dermatitis herpetiformis patients, and 34 EMA/ARA/JEA negative non-coeliac controls were tested. Methods: TG2 knockout (TG2−/−) and wild-type mouse oesophagus, jejunum, liver, and kidney sections, and TG2−/− sections coated with human recombinant TG2 were used as substrates in single and double immunofluorescent studies for patient IgA binding and tissue localisation of TG2, fibronectin, actin, and calreticulin. Results: None of the patient serum samples elicited EMA, ARA, or JEA binding in TG2−/− morphologically normal tissues. In contrast, 96 of 101 gluten sensitive patient samples (95%) reacted with wild-type mouse tissues and all 101 reacted in EMA/ARA/JEA patterns with TG2−/− mouse tissues coated with human TG2. Serum IgA binding to TG2−/− smooth muscle cells was observed in low titres in 31.1%, 27.5%, and 20.5%, and to TG2−/− epithelium in 26.3%, 5.0%, and 8.8% of coeliac, dermatitis herpetiformis, and control samples, respectively. These positivities partly colocalised with actin and calreticulin but not with TG2 or fibronectin. Conclusions: EMA/ARA/JEA antibody binding patterns are exclusively TG2 dependent both in coeliac and dermatitis herpetiformis patients. Actin antibodies are responsible for some positivities which are not part of the EMA/ARA/JEA reactions.


Cell Death & Differentiation | 1998

Retinoic acids regulate apoptosis of T lymphocytes through an interplay between RAR and RXR receptors

Zsuzsa Szondy; Uwe Reichert; László Fésüs

Vitamin A deficiency has been known for a long time to be accompanied with immune deficiency and susceptibility to a wide range of infectious diseases. Increasing evidence suggests that retinoic acids derived from vitamin A are involved in the functional regulation of the immune system. Of the two groups of retinoid receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs) all-trans and 9-cis retinoic acids are high affinity ligands for RARs and 9-cis retinoic acid additionally binds to RXRs. In cells, at high concentrations, all-trans retinoic acid can be converted to 9-cis retinoic acid by unknown mechanisms. Apoptosis plays a major role in shaping the T cell repertoire and one way in which retinoids may affect immune functions is to influence the various apoptosis pathways. Indeed, it has been shown that retinoic acids can induce apoptosis, increase the rate of dexamethasone-induced death and inhibit activation-induced death of thymocytes and T lymphocytes. Therefore, retinoids together with glucocorticoids may be involved in regulating positive and negative selection of T lymphocytes. Here we demonstrate that retinoids can induce apoptosis of T cells through the stimulation of RARγ. Specific stimulation of RARα, on the other hand, prevents both RARγ-dependent and TCR-mediated cell death. In all these functions 9-cis retinoic acid proved to be more effective than all-trans retinoic acid suggesting the involvement of RXRs. Based on these results a possible mechanism through which costimulation of RARs and RXRs might affect spontaneous and activation-induced death of T lymphocytes is proposed.


Journal of Immunology | 2011

Involvement of Adenosine A2A Receptors in Engulfment-Dependent Apoptotic Cell Suppression of Inflammation

Krisztina Köröskényi; Edina Duró; Anna Pallai; Zsolt Sarang; Doris Kloor; David S. Ucker; Susana Beceiro; Antonio Castrillo; Ajay Chawla; Catherine Ledent; László Fésüs; Zsuzsa Szondy

Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble “find me” signals, 2) recognition and phagocytosis via cell surface-presenting “eat me” signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A2A receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor δ. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation.


Cell Death & Differentiation | 2006

Tissue transglutaminase (TG2) protects cardiomyocytes against ischemia/reperfusion injury by regulating ATP synthesis.

Zsuzsa Szondy; Pier G. Mastroberardino; Judit Váradi; Maria Grazia Farrace; Norbert Nagy; Istvan Bak; Irene Viti; M. R. Wieckowski; Gerry Melino; Rosario Rizzuto; Arpad Tosaki; László Fésüs; Mauro Piacentini

Tissue transglutaminase (TG2) protects cardiomyocytes against ischemia/reperfusion injury by regulating ATP synthesis


FEBS Letters | 1997

Differential expression of tissue transglutaminase during in vivo apoptosis of thymocytes induced via distinct signalling pathways

Zsuzsa Szondy; Peter Molnar; Zoltán Nemes; Michael Boyiadzis; Noemi Kedei; Réka Tóth; László Fésüs

© 1997 Federation of European Biochemical Societies.


Hepatology | 2005

Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas‐mediated cell death in mice

Zsolt Sarang; Peter Molnar; Tamás Németh; Szabolcs Gomba; Tamás Kardon; Gerry Melino; Susanna Cotecchia; László Fésüs; Zsuzsa Szondy

Tissue transglutaminase (TG2) is a protein cross‐linking enzyme known to be expressed by hepatocytes and to be induced during the in vivo hepatic apoptosis program. TG2 is also a G protein that mediates intracellular signaling by the alpha‐1b‐adrenergic receptor (AR) in liver cells. Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti‐Fas antibodies to mice causes both disseminated endothelial cell apoptosis and fulminant hepatic failure. Here we report that an intraperitoneal dose of anti‐Fas antibodies, which is sublethal for wild‐type mice, kills all the TG2 knock‐out mice within 20 hours. Although TG2−/− thymocytes exposed to anti‐Fas antibodies die at the same rate as wild‐type mice, TG2−/− hepatocytes show increased sensitivity toward anti‐Fas treatment both in vivo and in vitro, with no change in their cell surface expression of Fas, levels of FLIPL (FLICE‐inhibitory protein), or the rate of I‐κBα degradation, but a decrease in the Bcl‐xL expression. We provide evidence that this is the consequence of the impaired AR signaling that normally regulates the levels of Bcl‐xL in the liver. In conclusion, our data suggest the involvement of adrenergic signaling pathways in the hepatic regeneration program, in which Fas ligand‐induced hepatocyte proliferation with a simultaneous inhibition of the Fas‐death pathway plays a determinant role. (HEPATOLOGY 2005.)


Frontiers in Immunology | 2014

Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications

Zsuzsa Szondy; Éva Garabuczi; Gergely Joós; Gregory J. Tsay; Zsolt Sarang

In healthy individuals, billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis) must be efficient to prevent secondary necrosis and the consequent release of pro-inflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and/or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes, or atherosclerosis. During the past decade, our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases.

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Uwe Reichert

Free University of Berlin

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Éva Garabuczi

Hungarian Academy of Sciences

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Beáta Kiss

University of Debrecen

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Ildikó Kiss

Hungarian Academy of Sciences

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Serge Michel

Centre national de la recherche scientifique

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Eva Szegezdi

National University of Ireland

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Beáta Tóth

Hungarian Academy of Sciences

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