Abstract
Purpose :
The lacrimal gland (LG) is the exocrine tubuloacinar gland that secretes tears. LG chronic inflammation induced by autoimmune disease or aging impairs tear secretion and causes dry eye disease. Current treatments alleviate symptoms but do not restore LG function, which could be improved by better understanding the mechanisms promoting inflammation. As aberrant inflammasome activation was shown in autoimmunity and age-related diseases, we analyzed the inflammasome pathway in inflammation models and investigated potential modulators.
Methods :
We used immunodetection and the R26-CAG-ASC-citrine mouse to detect inflammasomes, a fluorescent reporter of inflammasome complex activation. Acute LG injury was induced by IL-1a injection, and we used RT-qPCR and published RNA-seq data (GSE99093) for gene expression analysis. Chronic inflammation was studied in diabetes-free NOD.B10.H2b (NOD) mice compared to BALBc mice, and their LG transcriptome was analyzed by RNA-seq at 2, 4, and 6 months old. Sequencing data were processed with Rosalind software platform.
Results :
The number of ASC specks in LG epithelium was increased by acute or chronic inflammation. Several types of inflammasome sensors were upregulated in inflamed LGs, including Nlrp3, Aim2, and Ifi204. This was associated with an upregulation of the inflammasome effectors Casp1 and Casp4, along with the downstream pro-inflammatory interleukin genes Il1b and Il18, thus suggesting that they are functional. Inflammasome activation following IL-1a-injury preceded epithelial cell death and immune infiltration. We also found that the lipid metabolism pathway genes were upregulated after IL-1a-injury, during the switch from the primary inflammatory response to the tissue repair process. By contrast, Srebf1 and genes involved in fatty acid synthesis were downregulated during chronic inflammation, whereas the expression of lipid transporters and genes promoting the generation of cholesterol was increased.
Conclusions :
Epithelial cells can sense tissue injury and may contribute to the development of chronic inflammation by activating the inflammasome signaling pathway. During inflammation, various types of inflammasomes are activated in the LG, thereby illustrating the complexity of the inflammatory response. Altered lipid metabolism might trigger epithelial cell damage that sustains inflammasome activation, promoting LG chronic inflammation.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.