Identification Of Cell Polarity And Mechanosensing Defects In Sjogren’s Syndrome

Sjogren’s Syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and secretory dysfunction of exocrine tissues, including salivary glands. Our initial findings revealed defects in E-cadherin- and ZO-1-mediated cell-cell junctions in a NOD mouse model of SS and in human SS specimens, suggesting that secretory dysfunction was a consequence of structural defects and loss of cell polarity. Indeed, previous studies using a NOD mouse model of SS showed no apparent correlation between lymphocytic infiltration and secretory dysfunction.  

Objective: To identify cell biological defects in SS, we assessed the localization of TAZ, a transcriptional coactivator with key roles in cell polarity and in mechanosensing the extracellular matrix (ECM) stiffness. We aligned changes in TAZ localization with those in fibronectin, a component of the ECM, and in matrix metalloproteinase 9 (MMP9) that functions in the remodeling of the ECM. 

Method: Formalin-fixed and paraffin-embedded minor labial salivary gland SS specimens and non-compatible controls were stained for ZO-1, E-cadherin, β-catenin, MMP-9, fibronectin and TAZ using indirect immunofluorescence and analyzed by confocal microscopy. 

Result: In a subset of SS specimens, E-cadherin, β-catenin and ZO-1 exhibited disrupted staining. Fibronectin organization was less prominent, displaying a punctate pattern surrounding the acini. In contrast, MMP-9 was more pronounced in the basal regions of acini and colocalized with nuclei. Importantly, in SS specimens TAZ was less localized to cell-cell borders, exhibiting more nuclear and cytoplasmic staining, suggesting that the observed changes in the ECM and polarity were linked to its altered distribution.   

Conclusion: Our studies show for the first time that structural defects in a subset of SS phenotypes may be associated with changes in the distribution of TAZ, a regulator of cell polarity and a sensor of mechanical cues.