Tear Proteomics Reveals RAGE and NLRP3 Inflammasome Pathway Activation in Lacrimal Glands of a Sjögren’s Disease Mouse Model

作者：Xiaoyang Li, Mario Alba, Daniel J. Fernandez, Alison V. Ramirez, Sara Abdelhamid, Chenyi Wang, Maria C. Edman, Julian Whitelegge, Sarah F. Hamm‐Alvarez · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.15.738677 · 研究领域：Ocular Surface and Contact Lens、Salivary Gland Disorders and Functions、Advanced Glycation End Products research

ABSTRACT Purpose To characterize tear proteome changes in male non-obese diabetic (NOD) mice with Sjögren’s disease (SjD)-like autoimmune dacryoadenitis and determine whether identified tear proteins are associated with lacrimal gland (LG) pathogenesis. Methods Tears were collected from 14-week-old male NOD mice and age-matched male BALB/c controls and analyzed by tandem mass tag (TMT)-based liquid chromatography tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were defined using adjusted P < 0.05 and absolute fold change > 1.5. Functional enrichment analysis was performed using Enrichr. Selected upregulated DEPs were further examined in tear and LG samples from independent mouse cohorts using Western blotting, immunofluorescence, and RT-qPCR. Results A total of 142 proteins were quantified across all tear samples. Hierarchical clustering and principal component analysis (PCA) separated NOD from BALB/c tear proteomes. A total of 41 proteins were differentially expressed in NOD mouse tears (33 increased, 8 decreased). Increased tear proteins were enriched in immune and inflammatory responses, secretory compartments, RAGE receptor binding, glutathione metabolism, oxidative stress, and redox regulation. S100A8/A9, GSTO1-1, Gal-3, and pIgR/secretory component (SC) were increased in both NOD mouse tears and LG. In NOD LG, increased S100A8/A9 was accompanied by elevated RAGE, whereas increased GSTO1-1 was associated with increased NLRP3, cleaved c...