https://scholars.lib.ntu.edu.tw/handle/123456789/560673
標題: | Dual immuno-renal targeting of 7-benzylidenenaltrexone alleviates lupus nephritis via FcγRIIB and HO-1 | 作者: | Tseng, T.-C. Huang, D.-Y. LIANG-CHUAN LAI Hwai, H. Hsiao, Y.-W. Jhou, J.-P. Chuang, E.Y. ERIC YAO-YU CHUANG |
公開日期: | 2018 | 卷: | 96 | 期: | 5 | 起(迄)頁: | 413-425 | 來源出版物: | Journal of Molecular Medicine | 摘要: | 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. ? 2018, Springer-Verlag GmbH Germany, part of Springer Nature. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/560673 | ISSN: | 9462716 | DOI: | 10.1007/s00109-018-1626-9 | SDG/關鍵字: | 7 benzylidenenaltrexone; autoantibody; CD19 antigen; Fc receptor IIb; heme oxygenase 1; mitogen activated protein kinase p38; naloxone; naltrindole; 7-benzylidenenaltrexone; autoantibody; benzylidene derivative; Fc receptor; FCGR3B protein, human; glycosylphosphatidylinositol anchored protein; heme oxygenase 1; Hmox1 protein, mouse; membrane protein; naltrexone; animal cell; animal experiment; animal model; animal tissue; antigen expression; Article; B lymphocyte; cell count; controlled study; drug efficacy; drug safety; enzyme linked immunosorbent assay; female; flow cytometry; gene expression; immunocompetent cell; immunohistochemistry; immunosuppressive treatment; kidney fibrosis; kidney proximal tubule; lymphadenopathy; mouse; nonhuman; proteinuria; renal protection; spleen cell; splenomegaly; surface property; systemic lupus erythematosus; treatment outcome; upregulation; urine biochemistry; animal; blood; cell line; drug effect; immunology; kidney; lupus erythematosus nephritis; metabolism; Murphy Roths large lymphoproliferative mouse; pathology; spleen; Animals; Autoantibodies; B-Lymphocytes; Benzylidene Compounds; Cell Line; Female; GPI-Linked Proteins; Heme Oxygenase-1; Kidney; Lupus Nephritis; Membrane Proteins; Mice, Inbred MRL lpr; Naltrexone; Receptors, IgG; Spleen |
顯示於: | 藥理學科所 |
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