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Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Jin-Ping Li)ORCID iD: 0000-0003-1145-6700
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Stellan Sandler)
Swedish Univ Agr Sci, Immunol Sect, Dept Biomed Sci & Vet Publ Hlth, VHC, Box 7028, Uppsala, Sweden.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46229Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 7, article id 46229
Keywords [en]
Collagen-induced arthritis, Heparanase, Heparan Sulfate, Flow cytometry, T cells
National Category
Immunology in the medical area
Research subject
Immunology; Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-315694DOI: 10.1038/srep46229ISI: 000398988100001PubMedID: 28401953OAI: oai:DiVA.org:uu-315694DiVA, id: diva2:1075439
Funder
Swedish Research Council, 2015-02595; K2012-56X-15046-09-4Swedish Research Council, 521-2011-3533Swedish Heart Lung Foundation, 20140131Swedish Cancer Society, 150815Swedish Diabetes AssociationSwedish Child Diabetes FoundationAvailable from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-01-13Bibliographically approved
In thesis
1. Implications of Heparan Sulfate and Heparanase in Inflammatory Diseases
Open this publication in new window or tab >>Implications of Heparan Sulfate and Heparanase in Inflammatory Diseases
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1303
Keywords
Heparanase, Heparan sulfate, Inflammation, Inflammatory diseases, Autoimmune diseases, Amyloidosis, Reumathoid arthritis, SAA, APP, A beta, Neuroinflammation
National Category
Basic Medicine
Research subject
Medical Science; Medical Biochemistry; Immunology; Neurology
Identifiers
urn:nbn:se:uu:diva-315699 (URN)978-91-554-9828-3 (ISBN)
Public defence
2017-04-07, A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2017-03-17 Created: 2017-02-20 Last updated: 2018-01-13

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