JUND-DNAJB1-p21 axis drives fibroblast senescence to recruit CD4⁺ T cells in salivary gland pathogenesis of Sjögren’s disease

Abstract

Advanced age is a recognized risk factor for primary Sjögren’s disease (pSjD), suggesting a role for aging-related mechanisms in its pathogenesis. However, whether cellular senescence directly drives autoimmune inflammation and glandular dysfunction remains unclear. Furthermore, the specific role of senescent fibroblasts within the pSjD microenvironment has not been defined. This study investigates the mechanisms underlying fibroblast senescence and its therapeutic potential in pSjD. The senescence landscape of salivary glands was assessed by immunohistochemistry, multiplex immunofluorescence, and single-cell RNA sequencing, coupled with computational trajectory and gene regulatory network inference. In vitro, primary salivary gland fibroblasts (SGFs) were treated with interferon-gamma (IFN-γ). Senescence-associated β-galactosidase staining, reactive oxygen species detection, siRNA knockdown, co-immunoprecipitation, dual-luciferase reporter, and transwell migration assays were conducted to elucidate the underlying mechanisms. In vivo, a non-obese diabetic (NOD) mouse model was utilized to evaluate the efficacy of a senolytic combination (dasatinib and quercetin) on salivary flow rates and lymphocytic infiltration. Integrative analysis of human clinical samples and scRNA-seq revealed a significant accumulation of senescent fibroblasts in pSjD salivary glands. Pharmacological clearance of senescent cells in NOD mice significantly attenuated lymphocytic infiltration and restored salivary function, supporting a pathogenic contribution of fibroblast senescence. Subsequent computational trajectories and in vitro validations identified a senescence-enriched DNAJB1 high fibroblast subpopulation. Mechanistically, IFN-γ upregulated DNAJB1 transcription via JUND, which was in turn associated with p21-mediated senescence and enhanced CD4⁺ T cell recruitment. Furthermore, in vivo evaluations confirmed that the senolytic intervention effectively suppressed the glandular JUND-DNAJB1-p21 axis, corroborating the mechanistic findings. These findings indicate that the JUND-DNAJB1-p21 axis contributes to fibroblast senescence and autoimmune pathogenesis in pSjD. Senolytic clearance of senescent cells may represent a potential therapeutic strategy for mitigating glandular dysfunction.