Loss of STIM1/2 in salivary glands disrupts ANO1 function but does not induce Sjögren’s syndrome.

ABSTRACT: Primary Sjogren’s syndrome (pSS) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been considered a driver in pSS development. Saliva production is regulated by sympathetic input into the gland initiating intracellular Ca2+ signals that activate the store operated Ca2+ entry (SOCE) pathway eliciting sustained Ca2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models or its impact on pSS. Here we report that male and female mice lacking Stim1 and Stim2 (Stim1/2K14Cre) in salivary glands hyposalivate upon pilocarpine stimulation and showed reduced intracellular Ca2+ levels via SOCE in parotid acini. Bulk RNASeq of the parotid glands of Stim1/2K14Cre showed a decrease in Stim1/2 genes but not in other Ca2+ associated genes mediating saliva fluid secretion, yet SOCE was functionally required for the activation of the Ca2+ activated chloride channel ANO1. Ageing Stim1/2K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum which may be linked to the downregulation of the toll-like receptor 8 (Tlr8) in Stim1/2K14Cre mice. This is supported by an increase in TLR8 gene expression in a salivary gland cell line following SOCE stimulation. Moreover, salivary gland biopsies of pSS patients showed increased STIM1 and TLR8 expression. These results implicate SOCE as an important activator of ANO1 and saliva fluid secretion in salivary glands but loss of SOCE does not result in pSS. Importantly, our data suggest a link between SOCE and TLR8 signaling which may have implications in inflammatory responses in salivary glands.

ORGANISM(S): Mus musculus

PROVIDER: GSE251691 | GEO | 2025/02/19

REPOSITORIES: GEO