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

Abstract

Background Current research suggests that the glial scar surrounding penetrating brain injuries is instrumental in preserving the surrounding uninjured tissue by limiting the inflammatory response to the injury site. We recently showed that tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6), a well-established anti-inflammatory molecule, is present within the glial scar. In the present study we investigated the role of TSG-6 within the glial scar using TSG-6 null and littermate control mice subjected to penetrating brain injuries. Results Our findings show that mice lacking TSG-6 present a more severe inflammatory response after injury, which was correlated with an enlarged area of astrogliosis beyond the injury site. Conclusion Our data provides evidence that TSG-6 has an anti-inflammatory role within the glial scar.

Recent advances in mesenchymal stem/stromal cells (MSCs)‐based approaches for osteoarthritis (OA) therapy

“…TSG6 also inhibits interrelation between TLR4 with MyD88, thus constraining NF‐κB activation (Mittal et al, 2016). It also decreases proinflammatory proteins and conversely stimulates anti‐inflammatory proteins in macrophages (Bryan et al, 2019; Mutoji et al, 2021). In addition to paracrine effects, cell‐to‐cell contact mediated by intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 is required for MSCs‐mediated immunoregulatory impacts on T cells (Zhao et al, 2020).…”

Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6): A Promising Immunomodulatory Target in Acute Neurodegenerative Diseases

“…Either brain or spinal cord injury resulted in considerable upregulation of TSG-6 mRNA expression, whereby the protein is associated with the glial scar, likely playing a role in formation and stabilization of this HA-rich matrix forming an immunosuppressive environment [ 92 , 172 ]. Upon binding to inflammatory cells, these TSG-6 modified HA matrices modulate their responses, thus contributing to pathological inflammation [ 100 , 101 ].…”

“…Upon binding to inflammatory cells, these TSG-6 modified HA matrices modulate their responses, thus contributing to pathological inflammation [ 100 , 101 ]. Accordingly, elevation of endogenous TSG-6 mRNA was recently found in the lesioned hemisphere of mice subjected to penetrating brain injury (PBI), an effect that was associated with an anti-inflammatory role of this protein in the glial scar [ 172 ]. Indeed, TSG-6 null mice display a more severe inflammatory response (i.e., higher levels of NF-κB, RANTES and IL-1β, as well as higher number of CD68+ activated microglia and macrophages) and increased glial scar deposition in the injured brain as compared to littermate control mice [ 172 ].…”

Endogenously-Produced Hyaluronan and Its Potential to Regulate the Development of Peritoneal Adhesions

“…Last, TSG-6 enables a direct crosslinking of HA chains to form elongated HA fibers through the self-association of the TSG-6 protein [ 44 ]. These HA modifications and crosslinking are suggested to be involved in the regulation of physiological (oocyte cumulus matrix expansion) as well as pathophysiological processes (arthritis, pulmonary infections, autoimmune diseases, or scarring) [ 45 , 46 , 47 , 48 , 49 ]. In their review, Day and de la Motte propose the hypothesis that HA crosslinking serves as a protective mechanism.…”