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Dual immuno-renal targeting of 7-benzylidenenaltrexone alleviates lupus nephritis via FcγRIIB and HO-1

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Abstract

Known as a selective δ1 opioid receptor (DOR1) antagonist, the 7-benzylidenenaltrexone (BNTX) is also a DOR1-independent immunosuppressant with unknown mechanisms. Here we investigated if BNTX could be beneficial for diseased MRL/lpr lupus mice. We treated mice with 0.5, 2, 5 or 10 mg/kg/day of BNTX for 2 weeks. At as low as 2 mg/kg/day, BNTX significantly improved splenomegaly and lymphadenopathy. Notably, B cell numbers, particularly autoreactive plasma cells, were preferentially reduced; moreover, BNTX enhanced surface expression of FcγRIIB, an immune complex (IC)-dependent apoptotic trigger of B cells. Consequently, serum autoantibody concentrations were significantly decreased, leading to diminished glomerular IC deposition and renal fibrosis, thereby improving proteinuria. Microarray and pathway analyses revealed heme oxygenase-1 (HO-1) and p38 MAPK as key mediators of BNTX-induced upregulation of FcγRIIB. Moreover, HO-1 expression was also induced by BNTX via p38 MAPK at renal proximal tubules to further cytoprotection. Taken together, we demonstrate that BNTX can alleviate lupus nephritis by reducing autoreactive B cells via FcγRIIB and by augmenting renal protection via HO-1. Accordingly, we propose a new strategy to treat lupus nephritis via such a dual immuno-renal targeting using either a single agent or combined agents to simultaneously deplete B cells and enhance renal protection.

Key messages

  • 7-Benzylidenenaltrexone (BNTX) alleviates lupus nephritis in diseased MRL/lpr mice.

  • BNTX reduces autoreactive plasma cell numbers and serum autoantibody titers.

  • BNTX upregulates FcγRIIB levels via p38 MAPK and HO-1 to reduce B cell numbers.

  • Reduction of immune complex deposition and fibrosis by BNTX improves proteinuria.

  • BNTX induces HO-1 via p38 MAPK to enhance protection of renal proximal tubules.

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Acknowledgements

This study was supported by research grants from the Ministry of Science and Technology of Taiwan (NSC99-2320-B-002-011 and MOST-105-2321-B-002-040). We thank Dr. Wan-Wan Lin for critical reading and comment on the manuscript, and Ms. Yu-Syuan You for excellent technical supports. We also would like to acknowledge the services provided by the First Core Laboratory at College of Medicine, National Taiwan University and the RCF7 Laboratory of Department of Medical Research at National Taiwan University Hospital.

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Authors and Affiliations

  1. Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan

    Tsung-Chih Tseng, Duen-Yi Huang, Haw Hwai, Jyun-Pei Jhou & Shiang-Jong Tzeng

  2. Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan

    Liang-Chuan Lai

  3. Bioinformatics and Biostatistics Core, Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Liang-Chuan Lai, Yi-Wen Hsiao & Eric Y. Chuang

  4. Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

    Eric Y. Chuang

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  1. Tsung-Chih Tseng
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Supplemental Fig. 1

Serum ALT levels were not increased by BNTX treatment in MRL/lpr mice. Before and after control (vehicle, n = 6) or BNTX (2, 5, 10 mg/kg/day, n = 6) treatments, serum levels of ALT (P = 0.2361, 0.0174, 0.5061 and 0.2582) of MRL/lpr mice were examined for hepatotoxicity. Normal range of mouse serum ALT levels: 17–77 IU/L. (GIF 22 kb)

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Tseng, TC., Huang, DY., Lai, LC. et al. Dual immuno-renal targeting of 7-benzylidenenaltrexone alleviates lupus nephritis via FcγRIIB and HO-1. J Mol Med 96, 413–425 (2018). https://doi.org/10.1007/s00109-018-1626-9

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  • DOI: https://doi.org/10.1007/s00109-018-1626-9

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