Renal remodeling by CXCL10-CXCR3 axis-recruited mesenchymal stem cells and subsequent IL4I1 secretion in lupus nephritis

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外文摘要：Human umbilical cord mesenchymal stem cells(hUC-MSCs)have shown potential as a therapeutic option for lupus nephritis(LN),particularly in patients refractory to conventional treatments.Despite extensive translational research on MSCs,the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood.Here,we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment.This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10,predominantly produced by glomerular vascular endothelial cells through the IFN-γ/IRF1-KPNA4 pathway.Interestingly,the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes.Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment.Furthermore,hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1(IL4I1)in response to the microenvironment of LN kidney,thereby suppressing Th1 cells.Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3+Th1 cell infiltration into LN kidneys.This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment.Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN.

作者：

Qixiang Zhang、Yunlong Shan、Luping Shen、Qi Ni、Dandan Wang、Xin Wen、Huanke Xu、Xiaoyan Liu、Zhu Zeng、Jingwen Yang、Yukai Wang、Jiali Liu、Yueyan Su、Ning Wei、Jing Wang、Lingyun Sun、Guangji Wang、Fang Zhou

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作者单位：

Key Laboratory of Drug Metabolism and Pharmacokinetics,Haihe Laboratory of Cell Ecosystem,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing,China

Department of Pharmacy,Zhongshan Hospital,Fudan University,Shanghai,China

Department of Rheumatology and Immunology,The Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,China

Jiangsu Renocell Biotech Co.,Ltd.,Nanjing,China

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出版年：

2024

DOI：

10.1038/s41392-024-02018-5

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(12)