Zhou Cheng, Shang Shunlai, Zhao Jing, Yang Yunzhao, Shi Meihan, Li Ping, Li Qinggang, Zhang Jian, Li Wenge, Zhang Chuyue, Bai Xue-Yuan
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.
Research (Wash D C). 2025 Jul 10;8:0748. doi: 10.34133/research.0748. eCollection 2025.
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.
狼疮性肾炎被认为是系统性红斑狼疮常见且严重的并发症，目前尚无最佳治疗策略。虽然间充质干细胞（MSC）具有治疗潜力，但其疗效差异很大，这可能是由于它们的可塑性以及在不同微环境中转变为促炎（MSC1）或抗炎（MSC2）功能状态的能力。在此，我们首次报道，白细胞介素-27（IL-27）通过JAK1-STAT1信号通路，上调MSC中的吲哚胺2,3-双加氧酶（IDO），促使MSC向低免疫原性的IDO阳性MSC2表型分化。这些IDO阳性的MSC2细胞产生色氨酸的代谢产物犬尿氨酸和犬尿酸，它们与细胞内芳烃受体结合。这种相互作用刺激抗炎因子TSG-6增加，并诱导调节性T细胞分化。值得注意的是，在小鼠狼疮性肾炎模型中，经IL-27处理的MSC2与传统MSC相比，显示出更好的治疗效果。总之，本研究揭示IL-27是MSC免疫可塑性的关键调节因子，并提出了一种利用IL-27增强的MSC2治疗自身免疫性疾病的新策略。
