Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis

Andreas Digre,Kailash Singh,Stellan Sandler,Magnus Åbrink,Israel Vlodavsky,Jin-Ping Li,Rogier M Reijmers

doi:10.1038/srep46229

Andreas Digre, Kailash Singh + Show 5 more

Open Access

https://doi.org/10.1038/srep46229

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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.

Highlights

Dramatic increase in heparanase level (~100-fold) was detected in the synovial fluid and tissues from patients with Rheumatoid arthritis (RA), but not in osteoarthritis patients[12]
The pronounced inflammation in the joints of Heparanase transgenic mice (Hpa-tg) mice was further evidenced by histological analysis of sections from the joints (Supplementary Fig. S1a), showing that infiltration of inflammatory cells and the tissue damage were correlated with the clinical score
We found that proportions of Ly6G+, CD11b+ and CD11c+ cells were higher in the spleen and inguinal lymph nodes (ILNs) of Hpa-tg mice (Fig. 2a–c); while the percentage of plasmacytoid dendritic cells (pDCs) were higher in the thymus and ILNs of Hpa-tg mice in comparison to wild type (WT) mice (Fig. 2d)

Summary

Introduction

Dramatic increase in heparanase level (~100-fold) was detected in the synovial fluid and tissues from patients with RA, but not in osteoarthritis patients[12]. HSPGs have been found in chronically inflamed synovium[13], and the chemokine CXCL12 is expressed at high levels in synovial tissues of RA and is displayed on endothelial cells along with HSPGs14. Current knowledge strongly suggests a role for HS and heparanase in the pathogenesis of RA. By applying the collagen induced arthritis (CIA) model, we found that Hpa-tg mice displayed earlier and more severe clinical symptoms than WT mice. Our results suggest that heparanase may trigger and enhance both innate and adaptive immunity in response to inflammatory stimuli

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Conclusion