Traumatic brain injury (TBI) is a major medical concern that affects over 10 million people in the world each year (1, 2). A variety of injuries can cause TBI leading to a variety of injury severities (3–6). With improved medical interventions over the years the mortality rate due to TBI has decreased, culminating in a significant population living with the long-term effects of TBI. It is well accepted that in addition to the immediate effects of TBI there are also multiple potential long-term gradually evolving sequelae that are influenced by the type of injury, severity of injury and medical interventions at the time of injury (7, 8). Additionally, a link between mild traumatic brain injuries and Alzheimer or chronic traumatic encephalopathy has long been suspected (9). At present, long term effects of repeated TBI have been seen in multiple sports-related injuries, including post-traumatic parkinsonism, post-traumatic dementia and chronic post-concussion syndrome (10–13). Thus, studying the short and long-term consequences of TBI at a cellular and molecular level may lead to a new understanding and perhaps better long-term management of such injuries via new and/or refined treatment strategies.
Astrogliosis is a hallmark of TBI, which commences hours after injury and leads to an abnormal increase in the number of activated astrocytes in and around the injury site (14, 15). Immediately after injury (acute phase), astrocytes become highly proliferative and up-regulate the production of extracellular proteins, culminating in the formation of a glial scar, which impedes axonal growth, and therefore inhibits neuronal regeneration (14, 16–19). The intensity of the reactive astrogliosis directly affects the immediate and long-term effects of TBI (6, 15, 20, 21). Penetrating brain injuries (PBIs) cause direct parenchymal laceration, neuronal cell loss and hemorrhage, which lead to focal tissue damage at the injury site. Astrogliosis is triggered after PBIs and forms astrocyte-rich scar tissue surrounding the injury site (22–24). Mounting evidence shows that reactive astrocytes surrounding the injury site are instrumental in preserving the surrounding uninjured tissue by forming scar borders, which separate damaged and inflamed tissue from adjacent viable neural tissue (14, 15, 20, 25–29). Reactive astrocytes up-regulate intermediary filament proteins, Glial Fibrillary Acidic Protein (GFAP) and vimentin (VIM), as well as, increase production of chondroitin sulfate proteoglycans (CSPGs), all of which have been implicated in glial scar formation (30–35). Indeed, deficiency of both GFAP and VIM (Gfap−/−Vim−/−) leads to defective and less organized glial scarring in mice (34–36). Moreover, Wilhelmsson et al. observed that GfapP−/−Vim−/− mice exhibited increased axonal regrowth post injury in comparison to the wild-type control, suggesting that loss of these two proteins is enough to prevent glial scar formation and promote some neuronal regeneration (34). However, whether these mice present improved functional recovery compared to their littermates remains to be established. Recent work by the Sofroniew group has shown that scar tissue bordering the injury site is necessary for limiting inflammation and tissue damage to the injury site (26, 37). Moreover, data from Hermann et al. show that GFAP-driven ablation of STAT3 in astrocytes leads to the loss of lesion demarcation and subsequent glial scar formation, and, in turn, results in increased invasion of inflammatory cells into adjacent viable tissue and further spread of inflammation (38). This suggests that early demarcation from the glial scar formed by astrocytes restricts movement of inflammatory cells located within the lesion site into adjacent healthy tissue, thereby restricting tissue damage to the injury site. There is currently a significant number of studies investigating how reactive astrocytes regulate and limit inflammation in the injury site and which cellular components and major pathways play a part in this process (16, 37, 39–41).
(TNF)-stimulated gene-6 (TSG-6) is a 35-kDa protein that is secreted by a wide range of cell types in response to inflammatory mediators and growth factors (42). Originally identified as a gene product induced in fibroblasts by TNF (12), TSG-6 contains a link module domain that mediates interaction with the polysaccharide hyaluronan (HA) as well as other glycosaminoglycans (GAGs), which have served as targets in past experiments in attempts to promote neuronal regeneration after CNS injury (43–46). We recently identified that TSG-6 is expressed in the central nervous system (CNS), where it catalyzes the transfer of HCs from Inter-a-Inhibitor (IαI, also known as ITI) onto HA, forming a specialized HA/HC/TSG-6 matrix within the glial scar (47–52). This HA/HC/TSG-6 matrix is monocyte-adhesive and is found in most, if not all, inflammatory processes (53, 54). These TSG-6 modified HA matrices bind inflammatory cells, and the interaction of these cells with the HA matrices modulates their responses, which are central to pathological inflammation (55–61). Therefore, we postulate that TSG-6 could participate in the formation of an immunosuppressive environment within the glial scar. Thus, the main objective of this study was to have a better understanding of the role TSG6 plays in the glial scar. Our findings demonstrated that TSG-6 null mice present a more severe inflammatory response after injury when compared to littermate control mice. This increased inflammatory response is correlated with an enlarged area of astrogliosis beyond the injury site.