JAK inhibitor tofacitinib alleviates secretory dysfunction and Th17/Treg imbalance in a Sjögren's disease murine model.

Abstract

OBJECTIVES: To examine whether the JAK inhibitor tofacitinib alleviates secretory dysfunction and modulates Th17/Treg balance in a Sjögren's disease (SjD) murine model. METHODS: Integrated analysis of SjD transcriptome sequencing (GSE159574, GSE247662) identified key signalling pathways, potential therapeutic agents, and immune cell infiltration. NOD/ShiLtj mice were administered with or without tofacitinib. Secretory function and inflammation were assessed via fluorescein ocular surface staining, tear flow rate, histopathology (HE, Masson, Sirius Red), saliva flow rate, immunohistochemistry, immunofluorescence, flow cytometry, and cytokine measurement. Pearson's linear regression evaluated the correlation between Th17/Treg balance and secretory function. RESULTS: Bioinformatics analysis showed the JAK-STAT pathway and CD4+ T cells contribute to SjD pathogenesis. Tofacitinib reduced corneal fluorescein staining, increased tear break-up time and secretion, diminished salivary gland lymphocytic inflammation, improved saliva flow rate, and altered phospho-JAK3-STAT1 expression. It also reduced Th17 cell proportion, increased Treg cell proportion in salivary glands and spleens, decreased IL-17, and increased IL-10 and TGF-β in blood. A strong negative correlation existed between secretory function and Th17/Treg balance. CONCLUSIONS: Tofacitinib potently attenuated secretory dysfunction and inflammation in SjD mice, possibly by modulating Th17/Treg balance, suggesting it may be a therapeutic agent for SjD.