Transcriptomic changes in the lacrimal glands of a Sjogren's disease animal model highlight key molecular mediators and altered biological functions underpinning glandular inflammation and hypofunction.

INTRODUCTION

Sjogren's disease (SjD) is a chronic autoimmune condition that targets the lacrimal glands (LGs), resulting in aqueous-deficient dry eye disease (DED). Insufficient or low-grade tear secretion onto the ocular surface affects the normal physiology of the cornea and conjunctiva and can result in ocular surface damage. Herein, we evaluated the transcriptomic profiles of diseased versus healthy LGs to investigate the underlying molecular mechanisms underscoring LG autoimmune inflammation and secretory hypofunction.

METHODS

LGs were removed from male NOR/LtJ mice (SjD mouse model) and sex- and age-matched BALB/c controls at 3 weeks (pre-disease), 8 weeks (early disease onset), and 16 weeks (intermediately advanced disease stage). LGs were processed for either RNA extraction or histopathological staining. Bulk RNA sequencing was conducted for each LG sample followed by downstream data processing for differential expression analysis using the DESeq2 R package. Biological interpretation of the differential gene expression datasets was achieved using the QIAGEN Ingenuity Pathway Analysis (IPA) software. IPA was used to compare the differential gene expression results obtained in our analyses to those of previously published, publicly available datasets from other SjD-related transcriptomic-based studies.

RESULTS

The number of differentially expressed genes between NOR and BALB/c mice increased in correlation with the development and progression of dacryoadenitis. The most significantly upregulated pathways were primarily related to immune responses, emphasizing the activation of cellular and cytokine-mediated inflammatory responses. Several cytokines, transcription factors, and toll-like receptors were significantly predicted to drive most of the differential gene expression observed across our datasets. Biological processes involving the migration, recruitment, and activation of lymphocytes, but also lipid metabolism, were most significantly impacted in our disease model. Many of the identified dysregulated genes and affected biological functions were similarly regulated in the differential expression datasets of other transcriptomic-based studies of SjD patients and mouse models.

CONCLUSION

Chronic inflammation induces significant alterations to the LG transcriptome, promoting the recruitment of immune cells into the LG and the overactivation of inflammatory responses that severely impede normal secretory function. Future studies targeting some of the discovered key dysregulated molecules/pathways could open up potential therapeutic avenues for the treatment of chronic LG inflammation and secretory hypofunction.