Background/Purpose:  Sjögren’s syndrome (SS) patients manifest inflammation in salivary glands (SG) (lymphocytic infiltration of salivary and lachrymal glands) and evidence of intrinsic activation in the salivary epithelial cells (SGEC). Recent evidence from this laboratory has indicated that the aberrant exposure of SGEC of SS patients to necrotic debris may be a major cause of inflammatory reactions via the activation of inflammasome and may hold a key role in the pathogenesis of the disorder. Thrombospondin (TSP-1) is a matricellular glycoprotein with proinflammatory, antiangiogenic and proapoptotic properties. TSP-1 also activates TGF-β1 and has been shown to be involved in TH-17 response. It was originally characterized as an α-granule glycoprotein in platelets, although can be synthesized and released by a variety of cell types, including epithelial cells. Herein, we assessed the expression of TSP-1 in cultured ductal SGEC lines obtained from SS patients and controls. We also sought to investigate the effect of necrotic cell debris (NEC) on mRNA synthesis and release of TSP-1, in healthy epithelium.

Methods: non neoplastic SGEC lines from SS patients and non-SS controls (healthy) were comparatively evaluated for the constitutive expression of TSP-1 and IL-1β (both at mRNA and protein level in culture supernatants). In addition, SGEC lines treated with NEC were evaluated for the mRNA and protein expression of TSP-1 and IL-1β, by RT-PCT and ELISA, respectively.

Results: SS patients (n=14) displayed significant upregulation of TSP-1 mRNA levels in cultured epithelial cells, compared to controls (n= 10, p=0.0005), that correlated with the severity of histopathologic lesions (tarpley score of the respective Salivary Gland tissue biopsy) (Kruskal-Wallis test, p=0.001). SS-SGEC (n=16) were also found to secrete constitutively more TSP-1 and IL-1β in their culture supernatants, compared to non-SS SGEC (n=15) (p=0.0001 and p=0.06, respectively). There was a positive correlation among the constitutively expressed levels of TSP-1 and IL-1β (Spearman’s r= 0.66 for mRNA and r=0.41 for protein). Treatment of healthy SGEC lines (n=4) with NEC led to the induction of TSP-1 and IL-1β mRNA (2.1-fold and 2-fold increase, respectively), as well as protein in culture supernatants (3.0-fold and 2.5-fold increase, respectively) (for all comparisons, p<0.05), that were abrogated upon pre-treatment of NEC with DNase1.

Conclusion:  Preliminary results suggest for the first time that salivary gland epithelial cells from SS patients manifest increased TSP-1 and IL-1β levels that correlate with severe lymphocytic infiltrates in salivary glands. Chronic exposure to necrotic cells debris may hold a key pathogenetic role in the tissue inflammatory reactions of SS patients and may also explain the “intrinsic activation status” that characterizes the epithelia of these patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/thrombospondin-1-is-highly-expressed-by-salivary-gland-epithelial-cells-of-sjogrens-syndrome-patients-both-constitutively-and-upon-exposure-to-necrotic-cells-debris/