Abstract: FR-PO1029
Glutathione Synthesis Contributes to the Formation of Tertiary Lymphoid Tissues in the Kidney
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Arai, Hiroyuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto, Japan
- Yamamoto, Shinya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto, Japan
- Yoshikawa, Takahisa, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto, Japan
- Sugiura, Yuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan
- Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu Jinzo Naikagaku, Kyoto, Kyoto, Japan
Background
Tertiary lymphoid tissue (TLT) is an ectopic lymphoid tissue that is induced in non-lymphoid organs by several stimuli such as autoimmunity, aging, and chronic inflammation. TLTs serve as local sites for adaptive immune responses, in which vigorous lymphocyte proliferation and inflammatory cytokine production occur. Unlike the systemic activation of secondary lymphoid tissues, de novo formation of TLTs in local organs may require significant metabolic remodeling to meet the increased demand for metabolic resources both in parenchymal cells and immune cells. However, how renal parenchymal cells and locally recruited immune cells undergo metabolic alterations that support TLT formation remains to be elucidated.
Methods
We employed imaging mass spectrometry and metabolome analysis to investigate the key metabolic pathways that characterize renal TLTs. We also performed in situ hybridization combined with immunofluorescence to investigate the key molecules that govern the metabolic microenvironment of TLTs. Furthermore, we analyzed urine samples from both humans and mice to explore the metabolites that predict the presence of renal TLTs.
Results
Compared to other organs, the kidney contained more cysteine/cystine, a glutathione substrate. Kidneys with TLTs exhibited a significantly higher concentration of glutathione than normal kidneys, and high-level enrichment of glutathione was observed specifically in renal TLTs, highlighting the altered redox homeostasis within TLTs. DCs and fibroblasts within TLTs co-expressed xCT and MRP1, which are essential for external cystine intake and intercellular glutathione transport, respectively. Pharmacological inhibition of xCT prevented renal TLT formation, highlighting the importance of glutathione synthesis in renal TLT formation. Furthermore, enhanced glutathione synthesis in TLTs was reflected in the urinary glutathione concentrations in both mice and humans, indicating that urinary glutathione levels could effectively predict the presence or absence of renal TLTs.
Conclusion
We demonstrated that enhanced glutathione synthesis facilitates TLT formation in the kidney and that urinary glutathione can serve as a biomarker to detect renal TLTs. Immunometabolic interventions may provide new therapeutic strategies for kidney diseases.
Funding
- Government Support – Non-U.S.