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Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus

Cellular & Molecular Immunology volume 14, pages 842–849 (2017)Cite this article

Abstract

Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.

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Acknowledgements

We thank the health professional staff from Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital and the patients for their participation in this study. This study was supported by grants from the National Natural Science Foundation of China (81325019, 81630044, 81273312, 81601432, 81550023), the National Science Fund for Distinguished Young Scholars of China (813250046), Beijing Municipal Natural Science Foundation (7141008), the Research Special Fund for Public Welfare Industry of Health (20120217), and the Capital Health Research and Development of Special Fund (2011-4001-02).

Author contributions

All authors made substantial contributions. L-dZ and XZ conceived and directed the project and wrote the manuscript. DL and X-nW performed data input and statistical analysis. DL and YL performed flow cytometry experiments. The cell culture experiments were performed by J-wN. Western blotting was performed by CZ. RT-PCR was performed by HC. W-jZ and YL offered important suggestions. LW and Y-yF helped with clinical evaluations of the patients. F-lT and F-cZ collected samples. WH and X-tC provided the concept.

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  1. Li-dan Zhao, Di Liang and Xiang-ni Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China

    Li-dan Zhao, Di Liang, Xiang-ni Wu, Yang Li, Jing-wen Niu, Chen Zhou, Li Wang, Hua Chen, Wen-jie Zheng, Yun-yun Fei, Fu-lin Tang, Yong-zhe Li, Feng-chun Zhang & Xuan Zhang

  2. Department of Immunology, School of Basic Medicine, Peking Union Medical College, and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China

    Wei He & Xue-tao Cao

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  1. Li-dan Zhao
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Correspondence to Xuan Zhang.

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Zhao, Ld., Liang, D., Wu, Xn. et al. Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus. Cell Mol Immunol 14, 842–849 (2017). https://doi.org/10.1038/cmi.2016.47

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