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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

ABSTRACT: 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. The number of differentially expressed genes between NOR (diseased animal model/strain) and BALB/c (control strain) 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. Taken together, our data reveals that 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 impedes 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE309371 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Purpose: CD25KO mice have severe autoimmune disease and are used as a model of Sjögren disease, a prototype autoimmune dry eye. CD25KO mice have severe inflammation and infiltrating lymphocytes to multiple self-tissues, including the exocrine glands. We investigated the immunological profile of CD25KO mice and compared it to wild-type (WT) mice. Methods: 8-week-old WT and CD25KO mice were used. LGs (n=5) were submitted for RNA bulk sequencing. Tears washes were collected from mice and analyzed for protein expression using a luminex assay. A time course of adoptive transfer of CD25KO CD4+T cells was performed and LGs were evaluated by histology and qPCR. Co-adoptive transfer of CD25KO CD4+T cells with either 2M or 20M B6 CD25+GITR+T regulatory cells (Tregs) was performed in RAG1KO mice. LGs were evaluated in H&E-stained sections and by qPCR. Results: Investigation by RNA bulk sequencing found 3481 genes differentially expressed in CD25KO mice compared to B6, including upregulation of genes involved in T cell activation and Type I interferon signaling. CD25KO mice produced the same volume of tears as wild-type littermate controls, but had elevated protein expression of TNF, IFN-γ, and CCL5 and decreased protein expression of IL-12p40 and VEGF-A. Adoptive transfer recipients begin to develop inflammation and disease three weeks after adoptive transfer. In mice that received adoptive transfer of CD25KO CD4+ T cells, LGs had inflammation scores significantly higher than naive mice. They had increased expression of transcripts for inflammatory cytokines and chemokines. However, in recipient mice that received CD25KO CD4+T cells + 2M B6 Tregs, LGs had significantly reduced inflammatory scores and reduced expression of some inflammatory cytokines. Recipients of CD25KO CD4+T cells + 20M B6 Tregs had more inflamed lacrimal glands by both histology and qPCR, suggesting aged Tregs have less suppressive capacity.Conclusions: CD25KO mice have phenotypic and genetic changes resulting in increased inflammation, systemic autoimmunity and severe lymphocytic infiltration to the exocrine glands. These results are prominent in the tear film and LG. However, this autoimmunity can be controlled by addition of Tregs from healthy young mice, suggesting a possible avenue for therapeutic research.

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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

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