Tenascin-C: a marker and driver of inflammation
Item statusRestricted Access
Embargo end date04/07/2021
Ozanne, James Henry John
Tenascin-C, the founding member of the matricellular tenascin family, is a large multifunctional hexameric extracellular matrix (ECM) glycoprotein. It is abundantly expressed in the developing embryo but its expression becomes tightly regulated in the adult. However, during inflammatory responses tenascin-C becomes highly upregulated where it acts to create a local pro-inflammatory ‘niche’. In this proinflammatory role tenascin-C has been implicated in the pathogenesis of a variety of chronic inflammatory diseases including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), both of which are characterised by upregulated tenascin-C locally and systemically. The work of this thesis has looked to expand upon this earlier work, identifying tenascin-C as a key driver as well as marker of inflammation, and further probe its mechanistic role in the inflammatory response and utility as a biomarker of inflammatory disease. To answer the first question regarding tenascin-C’s role in pathological inflammation a murine Dextran Sulphate Sodium (DSS) model of chemically induced colitis was utilised. This thesis details the spatial and temporal expression of tenascin-C in the colon under basal conditions as well as the inflammatory state of the DSS model. Tenascin-C demonstrated a marked upregulation within the inflamed mucosa coinciding with the upregulation of other pro-inflammatory mediators and immune cell infiltration. Following this descriptive characterisation, subsequent studies probed the mechanistic relevance of this upregulation utilising the same model in combination with a tenascin-C knockout mouse. These studies showed a protective effect of tenascin-C’s genetic ablation on the severity of the colitis induced. This included reductions in gross pathology as well as histopathology including lower inflammation and tissue damage observed during the acute stage. Finally, with this mechanistic link clearly established between tenascin-C and the inflammatory diseased state this thesis aimed to explore tenascin-Cs utility as a disease marker, with a focus on RA. To this end, a number of novel immunoassays were established and validated for the measurement of tenascin-C and autoantibodies against in human serum samples. Screening of serum samples with these assays showed significantly higher levels of tenascin-C or autoantibodies against it in the serum of RA patients compared to healthy controls. These changes were not entirely RA specific however with a number of other inflammatory diseases tested also showing higher serum tenascin-C levels. The work described herein has utilised the DSS colitis model in combination with tenascin-C knockout mice to demonstrate the role of tenascin-C as a driver of inflammatory disease and has further shown translational relevance as a disease marker in human patients.