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Fibrotic Remodeling in the NOD/ShiLtJ Mouse Model of Sjögren’s Disease: Insights from Single-Cell Transcriptomics and AI-Driven Quantification

ABSTRACT: Sjögren’s Disease (SjD) is a systemic autoimmune disorder characterized by salivary gland hypofunction and lymphocytic infiltration, yet the contribution of fibrosis to glandular dysfunction remains unclear. The NOD/ShiltJ mouse is a well-established model for SjD. In this study, we evaluated the presence of and impact of fibrosis in the salivary glands of the NOD/ShiLtJ mouse. Using scRNASeq, we investigated differential gene expression in the fibroblasts of NOD mouse vs control mice. Fibroblast populations in the salivary glands of the NOD mouse exhibited increased levels of extracellular matrix mRNAs, including Col1a1, Col1a2, and Col3a1, relative to the control strain. From histological staining with Picrosirius red and AI-driven fibrosis quantification, we identified significant fibrotic remodeling in the submandibular glands of non-obese diabetic NOD/ShiLtJ mice relative to controls, which correlated with the diabetic phenotype in this mouse strain. We assessed the therapeutic potential of Nintedanib to alleviate this fibrotic phenotype. Nintedanib is an FDA-approved antifibrotic agent for chromic fibrosing interstitial lung disease. While Nintedanib did not significantly reduce immune infiltration or restore salivary function, it modestly decreased multiple fibrosis scores in long-term treatment cohorts. These findings demonstrate that the NOD/ShiLtJ strain models the fibrotic response that occurs in SjD patients and supports further investigation into antifibrotic therapies for salivary gland dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE314772 | GEO | 2026/06/19

REPOSITORIES: GEO

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Project description:Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth factor-beta 1 (TGFβ1). Existing therapies offer limited efficacy, particularly in advanced disease. Circadian rhythms have recently emerged as key modulators of lung inflammation and fibrosis. In this study, we developed an in vitro model of chronic fibrotic signaling using adenovirus-mediated TGFβ1 overexpression (Ad-TGFβ1) or human recombinant protein TGFβ1 in primary human lung fibroblasts. Using this model, we investigated the antifibrotic potential of STL1267, a next-generation Rev-erbα agonist with improved potency, specificity, and pharmacokinetic properties. RNA sequencing and pathway analysis revealed that STL1267 significantly reversed Ad-TGFβ1-induced expression of genes associated with ECM remodeling, collagen biosynthesis, and immune suppression. STL1267 also upregulated pathways related to IL-10, IL-4, and IL-13 signaling, which are known to counteract fibrotic responses. Quantitative PCR and immunoblotting confirmed STL1267's ability to downregulate key pro-fibrotic markers, including COL1A1, αSMA, FN1, and FAP, at both gene and protein levels. Comparative studies with other Rev-erbα agonists (GSK4112, SR9009), Saracatinib, and FDA-approved antifibrotic drugs (Pirfenidone, Nintedanib) demonstrated superior efficacy of STL1267 in inhibiting both preventive and post-fibrotic induction models. Moreover, lentiviral overexpression of Rev-erbα suppressed TGFβ1-induced αSMA expression, supporting a direct antifibrotic role. These findings highlight Rev-erbα as a key regulator of myofibroblast differentiation and support both STL1267 and GSK4112 as promising candidates for circadian-based antifibrotic therapy. Future in vivo studies are warranted to evaluate its translational potential in idiopathic pulmonary fibrosis.

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Fibrotic Remodeling in the NOD/ShiLtJ Mouse Model of Sjögren’s Disease: Insights from Single-Cell Transcriptomics and AI-Driven Quantification

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