SOCE as a Potential Key Factor in Sjögren’s Syndrome Pathogenesis

Objectives: Sjögren’s syndrome (SjS) is an autoimmune disease affecting 0.5-1% Americans, largely middle-aged women, characterized by lymphocytic infiltration in salivary and lacrimal glands. Clinical manifestations include dry mouth (xerostomia), dry eyes, swelling of glands, and caries. The molecular mechanisms underlying SjS are poorly understood. Store-operated Ca²⁺ entry (SOCE) is a major source of Ca²⁺ influx in cells and mediates fluid secretion. SOCE activation is regulated by the ER proteins STIM1 and STIM2 which bind to, and activate, the plasma membrane protein ORAI1. Our aim is to investigate the role of SOCE in the etiology of SjS and its effects on salivary gland (SG) function in a SOCE-deficient mouse strain. As SjS patients present with xerostomia prior to the onset of lymphocytic infiltration, we hypothesize that SOCE dysfunction in SG would lead to common SjS-like phenotypes.
Methods: We generated mice with a conditional deletion of Stim1 and Stim2 (Stim1/2^K14). We measured intracellular Ca²⁺ fluxes in SG cells using Fura2-AM following thapsigargin (TG) stimulation to activate SOCE. We analyzed the expression of Stim1/2 genes in SG by real time PCR and immunofluorescence. Pilocarpine was used to stimulate saliva flow. In un-stimulated mice, we obtained samples of the oral microbiome for 16s rRNA sequencing.
Results: SG of Stim1/2^K14 mice lacked STIM1/2 expression and abolished SOCE. Gland tissues appeared largely intact and the subcellular localization of Aquaporin 5 was not affected. Pilocarpine stimulation revealed significantly reduced saliva flow in Stim1/2^K14 mice. 16s rRNA sequencing showed that Stim1/2^K14 mice have altered composition of the oral microbiome.
Conclusions: Abolishing SOCE in SG cells of Stim1/2^K14 mice results in disrupted Ca²⁺ signaling, impaired SG function and altered oral microbiome. These features are associated with SjS, noticeable prior to lymphocytic infiltration of the SGs. We surmise that Stim1/2^K14 mice are an important new model for the study of SjS.