TGFβR Hyperactivation Drives CD103⁺/ITGB2⁺ TRM Cell Accumulation in High-Fat Diet-Exacerbated CIA

Obesity exacerbates rheumatoid arthritis (RA). However, the underlying mechanisms remain incompletely defined. Elucidating these mechanisms can help the identification of novel therapeutic targets. Herein, we used high-fat diet (HFD)-induced obese collagen-induced arthritis (CIA) mice to investigate these mechanisms. Immunohistochemistry revealed that obesity exacerbated joint inflammation and cartilage degradation. Next, integrated label-free quantitative proteomics and cytometry by time-of-flight (CyTOF) were used to characterize lymphocyte subsets. Proteomic profiling identified 26 differentially expressed proteins in obese versus lean CIA mice, including the transcription factors EOMES and KLF2, the TGFβ receptor (TGFβR) signaling component TGFBR2, and the tissue-resident memory (TRM) T cell marker CD103. CyTOF analysis revealed a robust 3.0-fold increase (P = 0.0043) in the proportion of CD103⁺ TRM cells among CD3⁺ T cells in obese CIA mice, characterized by a large effect size. Immunofluorescence results confirmed this increase in synovial tissues. Treatment with asiaticoside (a TGF-β/Smad-suppressing triterpenoid) significantly reduced TRM cell proportions (P < 0.05) and ameliorated symptoms in obese CIA mice. Collectively, these findings establish a novel mechanistic axis in which obesity-induced TGFβR-hyperactivation promotes TRM cell accumulation, which exacerbates arthritis severity in this RA model. Our findings provide a preclinical rationale for targeting TGFβR/TRM in human RA with obesity as a comorbidity.