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Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren's syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren's syndrome models: diseased NOD.H2 b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1 -/- ) compared to TSP-1 WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26 ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS/Nigericin, IL-1α and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1/4, and interleukins Il1b and Il18 . We also found increased IL-1β maturation in Sjögren's syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2 b lacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPARα)/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sjögren's syndrome-like pathogenesis in the NOD.H2 b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.

Sjögren's syndrome (SS) is a systemic autoimmune disorder affecting approximately 3% of the population in the United States. This disease has a female predilection and affects exocrine glands, including lacrimal and salivary glands. Dry eyes and dry mouths are the most common symptoms due to the loss of salivary and lacrimal gland function. Symptoms become more severe in secondary SS, where SS is present along with other autoimmune diseases like systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. It is known that aberrant activation of immune cells plays an important role in disease progression, however, the mechanism for these pathological changes in the immune system remains largely unknown. This review highlights the role of different immune cells in disease development, therapeutic treatments, and future strategies that are available to target various immune cells to cure the disease. [ABSTRACT FROM AUTHOR]