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- Digre, Andreas, 1987-
(författare)
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Implications of Heparan Sulfate and Heparanase in Inflammatory Diseases
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Digre, Andreas, 1987-, et al.
(författare)
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Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50 % of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+ and CD8+ T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.
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| 3. |
- Jendresen, Charlotte B., et al.
(författare)
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Overexpression of heparanase interferes with inflammatory-associated amyloid-beta clearance in mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Heparan sulfate proteoglycans (HSPGs) constitutes a major component in the plaques of amyloid-beta (Aβ), and heparanase degradation of HSPGs modulates deposition of Aβ in transgenic mice overexpressing Aβ precursor protein (AβPP) harboring Swedish mutation (tgSwe). In this study, we examined implications of heparanase expression in resolving/clearance of deposited Aβ in the tgSwe mice using an inflammation model induced by LPS-stimulation. Immunohistological staining of Aβx-40 and Aβx-42 showed reduced Aβ-burden in the brain of LPS-stimulated tgSwe in comparison to vehicle treated tgSwe. This reduction of Aβ-burden was evidenced by a significant decrease in the SDS and formic acid soluble Aβ in the brain lysate. In comparison, LPS-treatment had a marginal effect on Aβ-burden in the double transgenic (tgHpa*Swe) mice overexpressing both human heparanase and human AβPP. An immunological array analysis revealed an overall lower level of the inflammatory cytokines examined in the brain lysates of tgHpa*Swe mice, suggesting that heparanase overexpression attenuated inflammatory-associated clearance of deposited Aβ.
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