Abstract: TH-PO1143
Metabolic Landscape of Tertiary Lymphoid Structures in the Kidneys: Glutathione as a Key Regulator
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Arai, Hiroyuki, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Sugiura, Yuki, Kyoto University Center for Cancer Immunotherapy and Immunobiology, Kyoto, Japan
- Yamamoto, Shinya, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Yoshikawa, Takahisa, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Yanagita, Motoko, Kyoto University Graduate School of Medicine, Kyoto, Japan
Background
Tertiary lymphoid structure (TLS) is an ectopic lymphoid structure induced in non-lymphoid organs. TLSs serve as local sites for adaptive immune responses and are characterized by robust lymphocyte proliferation and cytokine production. During TLS formation, ectopic recruitment of hematopoietic cells implies a propensity for dramatic metabolic remodeling in both immune and parenchymal cells. However, the mechanism underlying TLS formation remains to be elucidated.
Methods
Imaging mass spectrometry and metabolomics were used to investigate the metabolic pathways that characterize TLSs. We also performed in situ hybridization combined with immunofluorescence and in vivo experiments to investigate the key molecules that govern the pivotal metabolic pathways of TLSs. Furthermore, we analyzed urine samples from both mice and humans to explore the metabolites that detect TLSs.
Results
Significant accumulation of glutathione was observed specifically within TLSs and the kidneys with TLSs exhibited higher glutathione concentrations than healthy kidneys. Compared to other organs, the kidney contained more cysteine/cystine, the crucial substrates for glutathione synthesis. TLSs also showed elevated oxidative stress, evidenced by increased 4-HNE and 8-OHdG levels. Immune cells within TLSs exhibited significantly higher oxidative stress than those in the spleen or peripheral blood. Dendritic cells and fibroblasts within TLSs selectively express xCT, an inducible cystine transporter that governs the rate limiting step of glutathione synthesis. Glutathione exchange between dendritic cells/fibroblasts and lymphocytes was observed in co-culture system. Pharmacological inhibition of xCT prevented TLS formation with enhanced cell death and oxidized lipid accumulation. Urinary glutathione levels significantly increased both in mice and humans with TLSs. In patients with IgA nephropathy, urinary glutathione combined with eGFR effectively detected TLSs in the kidney and significantly decreased following steroid treatment.
Conclusion
Glutathione accumulation is a distinctive metabolic signature of TLSs in the kidney. Glutathione synthesis plays a pivotal role in TLS formation, acting as a resilience mechanism to oxidative stress. Urinary glutathione may serve as a biomarker to detect TLSs in the kidney.
Funding
- Government Support – Non-U.S.