Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages

Department of Biochemistry and Molecular Biology, Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary.
Immunology letters (Impact Factor: 2.51). 12/2009; 130(1-2):74-81. DOI: 10.1016/j.imlet.2009.12.010
Source: PubMed


The multifunctional enzyme, transglutaminase 2 (TG2), can be found intracellularly, in the extracellular matrix and on the cell surface. Cell surface TG2 (csTG2) could not be detected by TG2-specific antibodies or autoantibodies on immunocompetent cells. A supposedly csTG2-specific antibody, 6B9, was recently shown to actually react with CD44. Though the importance of TG2-mediated deamidation of gluten in the pathogenesis of celiac disease has been well recognized, it is not known in which intestinal cells or cell compartment the deamidation occurs. Duodenal dendritic cells (DCs) can be directly involved in gluten-reactive T-cell activation. Here we use blood monocyte-derived dendritic cells (iDC) and macrophages (MPhi) as a model for intestinal antigen-presenting cells (APCs) and show that they contain large amounts of TG2. We found that TG100, a commercial TG2-specific monoclonal antibody can recognize TG2 on the surface of these cells, that is monocyte-derived APCs express surface-associated TG2. TG2 expression was found on the surface of individual tunica propria cells in frozen small bowel tissue sections from both normal and celiac subjects. We also demonstrate that the pool of TG2 on the surface of iDCs can be catalytically active, hence it might directly be involved in the deamidation of gliadin peptides. Bacterial lipopolysaccharide (LPS) increased the level of TG2 on the surface of maturing DCs, supporting the hypothesis that an unspecific inflammatory process in the gut may expose more transglutaminase activity.

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    • "The DQ2 and DQ8 α/β heterodimers in wheat gluten mediate the activation of glutenreactive CD4+T cells in the bowel [4]. HLA-DQ molecules as key steps leading to the intestinal inflammatory response on antigen-presenting cells specifically bind gluten-derived peptides, modified by the enzyme tissue transglutaminase (tTG) [2] [7] [8] [9], and present them to intestinal T cells [2] [4] [10]. Therefore, celiac disease is generally characterized by the production of anti-tissue transglutaminase (anti-tTG) [9] and anti-endomysial (EmA) antibodies [4] [10]. "

    Full-text · Article · Jan 2014
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    • "TG-2 is already known to have a role in DC function [8,10], although the full details of its role are yet to be determined. DCs have been found to increase the expression of TG-2 as their life cycle progresses, with particularly high levels during the final stages of maturation [10]. TG-2 may also play a part in DC maturation in response to LPS stimulation; recent research found increased levels of TG-2 subsequent to encountering LPS [8]. "
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    ABSTRACT: Dendritic cells (DCs) are part of the innate immune system with a key role in initiating and modulating T cell mediated immune responses. Coeliac disease is caused by inappropriate activation of such a response leading to small intestinal inflammation when gluten is ingested. Tissue transglutaminase, an extracellular matrix (ECM) protein, has an established role in coeliac disease; however, little work to date has examined its impact on DCs. The aim of this study was to investigate the effect of small intestinal ECM proteins, fibronectin (FN) and tissue transglutaminase 2 (TG-2), on human DCs by including these proteins in DC cultures. The study used flow cytometry and scanning electron microscopy to determine the effect of FN and TG-2 on phenotype, endocytic ability and and morphology of DCs. Furthermore, DCs treated with FN and TG-2 were cultured with T cells and subsequent T cell proliferation and cytokine profile was determined. The data indicate that transglutaminase affected DCs in a concentration-dependent manner. High concentrations were associated with a more mature phenotype and increased ability to stimulate T cells, while lower concentrations led to maintenance of an immature phenotype. These data provide support for an additional role for transglutaminase in coeliac disease and demonstrate the potential of in vitro modelling of coeliac disease pathogenesis.
    Full-text · Article · Apr 2012 · BMC Immunology
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    • "TG2 is mainly expressed intracellularly, but it can also be found extracellularly in the extracellular matrix [15]. In addition, it has been shown that TG2 is present on the surface of monocytes [16], monocyte-derived dendritic cells and macrophages [17], endothelial cells [18] and fibroblasts [19]. Since TG2 is present on the cell surface of these cell-types and has a Fn binding site located in the N-terminal domain, a prominent role for TG2 in mediating cell adhesion has been put forward [16], [19]. "
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    ABSTRACT: An important neuropathological feature of neuroinflammatory processes that occur during e.g. Multiple Sclerosis (MS) is the formation of an astroglial scar. Astroglial scar formation is facilitated by the interaction between astrocytes and extracellular matrix proteins (ECM) such as fibronectin. Since there is evidence indicating that glial scars strongly inhibit both axon growth and (re)myelination in brain lesions, it is important to understand the factors that contribute to the interaction between astrocytes and ECM proteins. Tissue Transglutaminase (TG2) is a multifunctional enzyme with an ubiquitous tissue distribution, being clearly present within the brain. It has been shown that inflammatory cytokines can enhance TG2 activity. In addition, TG2 can mediate cell adhesion and migration and it binds fibronectin with high affinity. We therefore hypothesized that TG2 is involved in astrocyte-fibronectin interactions. Our studies using primary rat astrocytes show that intracellular and cell surface expression and activity of TG2 is increased after treatment with pro-inflammatory cytokines. Astrocyte-derived TG2 interacts with fibronectin and is involved in astrocyte adhesion onto and migration across fibronectin. TG2 is involved in stimulating focal adhesion formation which is necessary for the interaction of astrocytes with ECM proteins. We conclude that astrocyte-derived TG2 contributes to the interaction between astrocytes and fibronectin. It might thereby regulate ECM remodeling and possibly glial scarring.
    Full-text · Article · Sep 2011 · PLoS ONE
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