Astrocyte-Derived Tissue Transglutaminase Interacts with Fibronectin: A Role in Astrocyte Adhesion and Migration?

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.

Subcellular localization patterns of transglutaminase 2 in astrocytes and neurons are differentially altered by hypoxia

“…Astrocytes were subjected to either serum starvation/normoxia or serum starvation/hypoxia, followed by surface biotinylation to isolate extracellular proteins. In agreement with previous studies using rat astrocytes [20], TG2 was present extracellularly in primary mouse astrocytes. The protein level of extracellular expression of TG2, however, was not altered in response to hypoxia (Figure 3B, C).…”

“…Astrocytes in post-mortem human brain samples from patients with multiple sclerosis express TG2, which colocalized with the extracellular protein fibronectin [19]. Furthermore, TG2 was externalized by primary rat astrocytes, where it colocalized with fibronectin and promoted adhesion and migration in response to treatment with inflammatory cytokines [20]. Interestingly, contrary to what has been found in astrocytes, there is no indication that TG2 is externalized by neurons.…”

Transglutaminase 2 interacts with syndecan-4 and CD44 at the surface of human macrophages to promote removal of apoptotic cells

“…Since TG2 cell surface activity has also been reported to be important in cell migration [12,43] we investigated the ability of TG2 inhibitors to modulate MØ migration towards AC using a horizontal migration chamber. We demonstrate that inhibition of TG2 reduces both the velocity and distance migrated by MØ in response to AC and results in a complete loss of directionality.…”

Transglutaminase-2 in cell adhesion

“…14,29 The effect of TG-2 on cell adhesion has been reported in NIH mouse 3T3 fibroblasts, 19 human umbilical endothelial cells, 29 human corneal epithelial cells, 24 astrocytes, 30 and a myelogenous leukemia cell line. 31 Despite the possible multiplicity of extracellular and intrinsic factors that exist in different tissues, some aspects of the TG-2-paxillin relationship 24 may be evolutionarily conserved.…”