Abstract: FR-PO1180
Elucidating Metabolic Microenvironment of Tertiary Lymphoid Structures in the Kidney
Session Information
- Top Trainee Posters - 4
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 12:00 PM - 01:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Arai, Hiroyuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan
- Sugiura, Yuki, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan
Background
Tertiary lymphoid structure (TLS) is an ectopic lymphoid structure induced in non-lymphoid organs by chronic inflammation. Functionally, 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 a considerable number of cells to non-lymphoid organs implies a propensity for dramatic metabolic remodeling in both immune and parenchymal cells. However, the mechanism underlying metabolic remodeling required for 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 pharmacological inhibition to explore the expression and function of 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 predict the presence of 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 displayed significant accumulation of 4-HNE and 8-OHdG, prominent markers of oxidative stress. Dendritic cells and fibroblasts within TLSs selectively express xCT, an inducible cystine transporter that governs the rate limiting step of glutathione synthesis. Pharmacological inhibition of xCT prevented TLS formation with enhanced cell death and oxidized lipid accumulation that promotes ferroptosis. Furthermore, urinary metabolite profiles significantly differed depending on the presence of TLSs both in mice and humans. In patients with IgA nephropathy, urinary metabolite profiles effectively detected TLSs in the kidney by multivariate logistic regression analysis.
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 and ferroptosis. Urinary metabolite profiles hold important clinical promise to identify TLSs in the kidney.
Funding
- Government Support – Non-U.S.