Pathogenic role of endogenous TNF-α in the development of Sjögren's-like sialadenitis and secretory dysfunction in non-obese diabetic mice

Abstract

Patients with Sjögren’s syndrome (SS), an autoimmune disease primarily affecting the exocrine glands, exhibit enhanced TNF-α expression in the saliva and salivary glands. However, the precise in vivo role of TNF-α during the initiation and development of SS is not clearly defined. The present study is undertaken to determine the function of endogenously produced TNF-α in the pathogenesis of SS in non-obese diabetic (NOD) mice, a model of this human disease. Administration of a neutralizing anti-TNF-α antibody to female NOD mice during the stage prior to disease onset significantly improved salivary secretion, indicating a remission of clinical symptoms of SS. TNF-α blockade also decreased the number of leukocyte foci and reduced the number of T cells and B cells in the submandibular glands. Moreover, TNF-α blockade reduced T-bet protein level in the submandibular glands, suggesting a decrease in T helper 1- and T cytotoxic 1 cells. These cellular changes induced by TNF-α neutralization were associated with a reduction in T and B cell chemoattractants CXCL9 and -13. In addition, TNF-α blockade markedly increased the expression level of tight junction protein claudin-1 and water channel protein aquaporin-5, two key factors required for normal salivary secretion, in the submandibular glands. Collectively, these findings indicate that endogenous TNF-α plays a pathogenic role in the development of SS in the NOD model of this disease.

Disruption of CXCR3 function impedes the development of Sjögren's syndrome-like xerostomia in non-obese diabetic mice

“…One intriguing finding in this study is that administration of anti-CXCR3 antibody exacerbates the production of ANA and anti-M3R autoantibodies. We and other groups have reported the negative correlation between the autoantibody production and TNF-α pathway [16,48,49]. We thereby speculate that the appearance of excessive autoantibodies caused by CXCR3 blockade is the consequence of diminished TNF-α production.…”

“…Expression of CXCL9, CXCL10, and CXCL11 can be up-regulated by pro-inflammatory cytokines, including IFN-γ and TNF-α, in a variety of cell types [13][14][15]. Consistent with this, our recent study demonstrated the down-regulation of CXCL9 in the salivary glands of an SS-like mouse model as a result of TNF-α blockade [16]. CXCR3 ligands play important roles in the pathogenesis of various inflammatory and autoimmune diseases [13,[17][18][19][20][21].…”

“…Elevated level of pro-inflammatory factor TNF-α has been detected in the salivary glands of SS patients [38]. Our recent report provided evidence that TNF-α is essential for the pathogenesis of SS through promoting CXCR3 ligand expression and facilitating T lymphocyte infiltration of the SMGs of NOD mice [16]. In the present work, we demonstrated that CXCR3 blockade in turn down-regulates TNF-α expression in the SMGs, indicative of a positive feed-forward loop formed between CXCR3 and TNF-α which amplifies salivary gland inflammation.…”

“…In the present work, we demonstrated that CXCR3 blockade in turn down-regulates TNF-α expression in the SMGs, indicative of a positive feed-forward loop formed between CXCR3 and TNF-α which amplifies salivary gland inflammation. Moreover, both TNF-α neutralization and CXCR3 blockade lead to increased claudin-1 and AQP5 levels in the SMGs [16], further suggesting a close interplay between TNF-α and CXCR3-mediated pathways. Claudin-1 is an essential component of intercellular tight junction, crucial for a well-regulated diffusion barrier between apical and basal regions of exocrine gland cells and the maintenance of water and solute exchange [41].…”

“…Excessive pro-inflammatory factor TNF-α has been detected in both salivary glands and blood of SS patients [37,38] and plays a pathogenic role in SS development in the NOD model of SS disease [16]. To assess whether CXCR3 blockade can diminish TNF-α production, we performed immunohistochemical staining of SMG sections, which showed that anti-CXCR3 treatment significantly reduced the TNF-α protein level (Fig.…”