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Implications of Heparan Sulfate and Heparanase in Inflammatory Diseases
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
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 [en]
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: urn:nbn:se:uu:diva-315699ISBN: 978-91-554-9828-3 (print)OAI: oai:DiVA.org:uu-315699DiVA, id: diva2:1075441
Public defence
2017-04-07, A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilAvailable from: 2017-03-17 Created: 2017-02-20 Last updated: 2018-01-13
List of papers
1. Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
Open this publication in new window or tab >>Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis
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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.

Keywords
Collagen-induced arthritis, Heparanase, Heparan Sulfate, Flow cytometry, T cells
National Category
Immunology in the medical area
Research subject
Immunology; Medical Science
Identifiers
urn:nbn:se:uu:diva-315694 (URN)10.1038/srep46229 (DOI)000398988100001 ()28401953 (PubMedID)
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 Foundation
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-01-13Bibliographically approved
2. Heparin interactions with apoA1 and SAA in inflammation-associated HDL
Open this publication in new window or tab >>Heparin interactions with apoA1 and SAA in inflammation-associated HDL
2016 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 474, no 2, p. 309-314Article in journal (Refereed) Published
Abstract [en]

Apolipoprotein A1 (apoA1) is the main protein component responsible for transportation of cholesterol on high-density lipoprotein (HDL). Serum amyloid A (SAA) is an acute phase protein associated with HDL. Apart from their physiological functions, both apoA1 and SAA have been identified as 'amyloidogenic peptides'. We report herein that the polysaccharide heparin interacts with both apoA1 and SAA in HDL isolated from plasma of inflamed mice. The reaction is rapid, forming complex aggregates composed of heparin, apoA1 and SAA as revealed by gel electrophoresis. This interaction is dependent on the size and concentration of added heparin. Mass spectrometry analysis of peptides derived from chemically crosslinked HDL-SAA particles detected multiple crosslinks between apoA1 and SAA, indicating close proximity (within 25 angstrom) of these two proteins on the HDL surface, providing a molecular and structural mechanism for the simultaneous binding of heparin to apoA1 and SAA.

Keywords
Heparan sulfate, Lipoproteins/receptors, Amyloid, Atherosclerosis, Proteoglycans, Mass spectrometry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-298081 (URN)10.1016/j.bbrc.2016.04.092 (DOI)000376221700013 ()27105909 (PubMedID)
Funder
Swedish Research Council, K2012-67X-21128-04-4Swedish Heart Lung Foundation, 20140131
Available from: 2016-06-30 Created: 2016-06-29 Last updated: 2017-11-28Bibliographically approved
3. Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases
Open this publication in new window or tab >>Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, article id e39899Article in journal (Refereed) Published
Abstract [en]

AA-amyloidosis is a disease characterized by abnormal deposition of serum A amyloid (SAA) peptide along with other components in various organs. The disease is a complication of inflammatory conditions that cause persistent high levels of the acute phase reactant SAA in plasma. In experimental animal models, the deposited amyloid is resolved when the inflammation is stopped, suggesting that there is an efficient clearance mechanism for the amyloid. As heparan sulfate (HS) is one of the major components in the amyloid, its metabolism is expected to affect the pathology of AA amyloidosis. In this study, we investigated the effect of heparanase, a HS degradation enzyme, in resolution of the AA amyloid. The transgenic mice deficient in heparanase (Hpa-KO) produced a similar level of SAA in plasma as the wildtype control (Ctr) mice upon induction by injection of AEF (amyloid enhancing factor) and inflammatory stimuli. The induction resulted in formation of SAA amyloid 7-days post treatment in the spleen that displayed a comparable degree of amyloid load in both groups. The amyloid became significantly less in the Hpa-KO spleen than in the Ctr spleen 10-days post treatment, and was completely resolved in the Hpa-KO spleen on day 21 post induction, while a substantial amount was still detected in the Ctr spleen. The rapid clearance of the amyloid in the Hpa-KO mice can be ascribed to upregulated matrix metalloproteases (MMPs) that are believed to contribute to degradation of the protein components in the AA amyloid. The results indicate that both heparanase and MMPs play important parts in the pathological process of AA amyloidosis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-194442 (URN)10.1371/journal.pone.0039899 (DOI)000306355500015 ()22808071 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council, K2009-67X-21128-01-3
Available from: 2013-02-14 Created: 2013-02-14 Last updated: 2018-01-11Bibliographically approved
4. Overexpression of heparanase interferes with inflammatory-associated amyloid-beta clearance in mice
Open this publication in new window or tab >>Overexpression of heparanase interferes with inflammatory-associated amyloid-beta clearance in mice
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keywords
Alzheimer's disease, APP mouse, Heparanase, Heparan sulfate, Neuroinflammation, Amyloidosis, Clearance, A beta
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-315696 (URN)
Funder
Swedish Research Council
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-01-13

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