Pos0812 binding of Cxcl13 With Heparan Sulfate of Syndecan-1 Plays an Important Role in Pathogenesis of Sjögren’s Syndrome

Abstract

BackgroundSjögren’s syndrome (SS) is a chronic autoimmune disorder with lymphocytic infiltration in exocrine and non-exocrine epithelia, in which epithelial cells play a critical role in the initiation and amplification of inflammatory processes. Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan predominantly expressed on epithelial cells and binds to and regulates heparan sulfate-binding molecules, such as chemokines.ObjectivesIn this study, we investigated the expression of SDC-1 and homeostatic chemokines and the colocalization and association of SDC-1 and B cell chemokines in mouse model of primary SS to define the role of SDC-1 in the pathogenesis of SS.MethodsFemale NOD/ShiLtJ between 6 and 12 weeks of age and sex-, and age-matched C57BL10 mice were used. Stimulated salivary flow rates (SFRs), histopathologic findings and expression of growth factor and chemokines were evaluated. Inflammation of the submandibular glands (SMGs) was assessed by the ratio index (the ratio of the area of inflammation to the total area of glandular tissue). SDC-1 level in SMGs and blood were analyzed using dot blot method. Immunofluorescence staining was performed for detection of colocalization of CXCL13 and SDC-1. For SDC-1 and CXCL13 coassociation experiments, immunoprecipitation assay was performed.ResultsThe mean SFR was significantly reduced in 12-week-old NOD mice (p=0.013). Periductal inflammatory cell infiltration was detected in the SMGs in 1 of 8 (12.5%) of the 6-week-old and in all of 12-week-old NOD mice. The mean ratio index was 0.1, 4.0, 7.1, and 10.2 in the 6-, 8-, 10-, and 12-week-old NOD mice, respectively. The expression of SDC-1 in inflamed SMGs of NOD mice was elevated, especially on the ductal epithelial cells, and tended to increase as the glandular inflammation progressed. Compared to controls, the concentration of SDC-1 in the SMGs and blood of NOD mice began to increase significantly from the age of 6 weeks (SMGs, 15.6±3.6 vs. 3.5±1.2, p=0.049; Blood, 17.4±1.3, 9.7±1.6, p=0.005). In the NOD mice, the concentration of SDC-1 of SMGs and blood began to be significantly different from the age of 10 weeks (6-week-old vs. 10-week-old mice, SMGs, 15.6±3.6 vs. 25.8±2.7, p=0.033; Blood, 17.4±1.3 vs. 27.7±1.2, p<0.001).Compared to controls, the expression of growth factors in NOD mice was reduced, while the expression of chemokines (CXCL12, CXCL13 and IL-7) and chemokine receptors (CXCR4, CXCR5) was increased. CXCL13 and SDC-1 were detected together on the surface of glandular epithelial cells in the SMGs by immunofluorescent staining. Furthermore, colocalization of SDC-1 and CXCL13 was confirmed by immunofluorescent staining using NMuMG cells which express SDC-1 abundantly. Immunoprecipitation studies demonstrated that SDC-1 formed complexes with CXCL13, which suggested that SDC-1 binds with CXCL13 directly through heparan sulfate on the surface of glandular epithelial cells and participates in an inflammatory pathway through B cell chemotaxis.ConclusionThese results suggested that increased SDC-1 expression in submandibular glands plays a role in the inflammatory processes through binding of SDC-1 with CXCL13 in pathogenesis of SS.References[1]Bartlett AH, Hayashida K, Park PW. Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol Cells 2007;24:153-66.[2]de Paz JL, Moseman EA, Noti C, Polito L, von Andrian UH, Seeberger PH. Profiling heparin-chemokine interactions using synthetic tools. ACS Chem Biol 2007; 2(11):735-44.[3]Barone F, et al. CXCL13, CCL21, and CXCL12 Expression in Salivary Glands of Patients with Sjo¨gren’s Syndrome and MALT Lymphoma: Association with Reactive and Malignant Areas of Lymphoid Organization. J Immunol 2008; 180: 5130-40.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Spotlight on Syndecan 1 Role in Systemic Autoimmune Rheumatic Diseases: Main Actor or Guest Appearance?

“…Emerging research has begun to highlight other biomarkers with significant implications for autoimmunity, including Syndecan-1 (SDC-1) [13][14][15]. Also known as CD138, SDC-1 is a transmembrane heparan sulfate proteoglycan ubiquitously found on the cell surface and nuclear membrane (Figure 1) [16].…”