Implications of Heparan Sulfate and Heparanase in Inflammatory Diseases

Heparan sulfate (HS), an unbranched sulfated carbohydrate chain, and the HS-degrading enzyme heparanase play important roles in physiological and pathological processes during all stages of life, from early embryogenesis to ageing. Accumulated information shows that HS and heparanase are involved in inflammatory processes and associated diseases, e.g. rheumatoid arthritis (RA) and Alzheimer’s disease. In this thesis I have investigated the role of HS and heparanase (Hpa) in inflammatory-related pathologies. In the first project, Hpa overexpressing mice (Hpa-tg) were induced with a murine model of RA. We found a pro-inflammatory role of Hpa through enhancing the activity of T-cells and innate immune cells, which contributed to an augmented severity of clinical symptoms in the Hpa-tg mice. In my second project, we revealed co-current interaction of heparin with both ApoA1 and SAA of HDL isolated from plasma of inflamed mouse. Mass spectrometry analysis indicated close proximity of ApoA1 and SAA on the HDL surface, providing a molecular and structural mechanism for the simultaneous binding of heparin to apoA1 and SAA. In my third project, we investigated the role of Hpa in AA amyloid formation and resolution in mice in a model of AA-amyloidosis. We found a similar degree of amyloid formation in Hpa-KO mice compared to the wildtype control mice, but the resolution process was faster in Hpa-KO mice. The rapid clearance of deposited SAA in Hpa-KO mice was associated with upregulated expression of matrix metalloproteases. The results suggest an associated function of ECM proteases with heparanase in the process of AA amyloid resolution. In my fourth project, we found that overexpression of heparanase impaired inflammation associated beta amyloid (Aβ) clearance in the brain of an Alzheimer’s disease mouse model. Examination of the cytokine profile of brain lysates revealed an overall lower inflammatory reaction in the double transgenic (tgHpa*Swe) mice compared to single APP-tg (tg-Swe) mice in response to LPS-induced inflammation