Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism

Abstract

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.H2b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1-/-) compared to TSP-1WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26ASC-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.H2blacrimal 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.H2b mouse lacrimal gland by promoting epithelial dysfunction and inflammation.

The First Transcriptomic Atlas of the Adult Lacrimal Gland Reveals Epithelial Complexity and Identifies Novel Progenitor Cells in Mice

“…Consistent with the previous notion that the LG is a part of the mucosal immune barrier system [54,105,106], our study revealed a substantial presence of resident immune cells from both the lymphoid and myeloid lineages in the gland. We recently showed that the epithelial LG cells are sentinel cells that can sense danger signals/tissue damage and recruit immune cells by activating the inflammasome pathway [107]. Therefore, it is not surprising to find a considerable number of innate immune cells and resident regulatory T cells in the LG in homeostatic conditions, as they can rapidly initiate an inflammatory response upon sensing alarm signals.…”

Advances in imaging of the lacrimal gland in Sjögren's syndrome: A narrative review

“…IFN-then induces the production of more alarmins in the extracellular environment by salivary gland epithelial cells, creating a damaging autoinflammatory loop that promotes local and systemic damage and results in the continuation of the disease. 39,40 with functional tests. The application of various imaging modalities in the evaluation of SS lacrimal gland lesions is detailed below.…”

“…Following their activation, plasmacytoid dendritic cells release large amounts of IFN‐α and B‐cell activating factor (BAFF), which aid in the proliferation of B cells inside the germinal center. IFN‐ then induces the production of more alarmins in the extracellular environment by salivary gland epithelial cells, creating a damaging autoinflammatory loop that promotes local and systemic damage and results in the continuation of the disease 39,40 …”