Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury

Abstract

Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) binds to hyaluronan and can reorganize/stabilize its structure, also enhancing the binding of this glycosaminoglycan to its cell surface receptor, CD44. TSG-6 is rapidly up-regulated in response to inflammatory cytokines protecting tissues from the damaging effects of inflammation. Despite TSG-6 treatment having been shown to improve outcomes in an experimental model of traumatic brain injury, TSG-6 expression has not been extensively studied in the central nervous system (CNS). We hereby analyzed the expression profile of TSG-6 in the developing CNS and following injury. We show that TSG-6 is expressed in the rat CNS by GFAP ؉ and CD44 ؉ astrocytes, solely in the mature brain and spinal cord, and is not present during the development of the CNS. TSG-6 ؊/؊ mice present a reduced number of GFAP ؉ astrocytes when compared with the littermate TSG-6 ؉/؊ mice. TSG-6 expression is drastically up-regulated after injury, and the TSG-6 protein is present within the glial scar, potentially coordinating and stabilizing the formation of this hyaluronan-rich matrix. This study shows that TSG-6 is expressed in the CNS, suggesting a role for TSG-6 in astrocyte activation and tissue repair. We hypothesize that within this context TSG-6 could participate in the formation of the glial scar and confer anti-inflammatory properties. Further studies are required to elucidate the therapeutic potential of targeting TSG-6 after CNS injury to promote its protective effects while reducing the inhibitory properties of the glial scar in axon regeneration.

Anti-inflammatory protein TNFa-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

“…Our data show an increase in TSG-6 expression in the injured hemisphere of Tsg-6 +/− mice after TBI. This increase in expression after CNS insults supports our earlier findings in a rat model that astrocytes secrete high levels of TSG-6 upon injury, which aids in the formation of a specialized HA/HC/TSG-6 matrix during an inflammatory response (47). As TSG-6 is known for having anti-inflammatory properties, to further study whether high levels of TSG-6 served a purpose of rapidly suppressing inflammation after injury, we performed similar penetrating injuries in Tsg-6 −/− mice.…”

“…versican and aggrecan), forming specific HA/HC/TSG-6 matrices (57, 72-76). Our previous study suggests these HA/HC/TSG-6 matrices could also support the glial scar (47). Therefore, given that TSG-6 directly binds to both CS and HA, these enzymatic treatments targeting the glial scar as a means to promote regeneration would also remove TSG-6, a known anti-inflammatory molecule that is also a component of the glial scar (74).…”

“…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)(44)(45)(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)(48)(49)(50)(51)(52). This HA/HC/TSG-6 matrix is monocyteadhesive and is found in most, if not all, inflammatory processes (53,54).…”

Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

“…There is currently a signi cant number of studies investigating how reactive astrocytes regulate and limit in ammation in the injury site and which cellular components and major pathways play a part in this process (16,37,(39)(40)(41). We recently found that tumor necrosis factor (TNF)stimulated gene-6 (TSG-6) is secreted by astrocytes after injury and is a major constituent of the glial scar, but the role it plays within the glial scar remains to be established (42).…”

Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

“…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)(44)(45)(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)(48)(49)(50)(51)(52). This HA/HC/TSG-6 matrix is monocyte-adhesive and is found in most, if not all, inflammatory processes (53,54).…”