System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 40642057 DOI: 10.34133/research.0748

IL-27 Modulates Mesenchymal Stem Cell Immunoplasticity for Enhanced Lupus Nephritis Therapy via the JAK1-STAT1-IDO Axis and Tryptophan Metabolic Orchestration.

Research (Wash D C) 8:0748

Authors: Cheng Zhou, Shunlai Shang, Jing Zhao, Yunzhao Yang, Meihan Shi, Ping Li, Qinggang Li, Jian Zhang, Wenge Li, Chuyue Zhang, Xue-Yuan Bai

Affiliations

  • Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.
  • Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk-2023310), Beijing 100853, China.
  • Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk-2023310), Beijing 100853, China. Department of Nephrology and Institute of Kidney Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

Lupus nephritis is recognized as a common and severe complication of systemic lupus erythematosus, without an optimal therapeutic strategy currently available. While mesenchymal stem cells (MSCs) hold therapeutic promise, their efficacy varies substantially, likely due to their plasticity and capacity to adopt pro-inflammatory (MSC1) or anti-inflammatory (MSC2) functional states in response to different microenvironments. Here, we report for the first time that IL-27, via JAK1-STAT1 signaling, up-regulates indoleamine 2,3-dioxygenase (IDO) in MSCs, driving MSC differentiation toward an IDO-positive MSC2 phenotype with low immunogenicity. These IDO-positive MSC2 cells produce kynurenine and kynurenic acid, the metabolites of tryptophan, which bind to the intracellular aryl hydrocarbon receptor. This interaction stimulates an increase in the anti-inflammatory factor TSG-6 and induces the differentiation of regulatory T cells. Notably, IL-27-conditioned MSC2 demonstrated superior therapeutic efficacy compared to conventional MSCs in a murine lupus nephritis model. In conclusion, this study revealed that IL-27 is a critical modulator of MSC immune plasticity and presented a novel therapeutic strategy utilizing IL-27-enhanced MSC2 for autoimmune diseases.

MeSH

Cells, Microscopy, Electron, Scanning Transmission, Tryptophan, Lupus Nephritis, Stem Cells, Mesenchymal Stem Cells, Interleukin-27, Therapeutics, Nephritis, Indoleamine-Pyrrole 2,3,-Dioxygenase