Advertisement

Journal of Molecular Medicine

, Volume 96, Issue 5, pp 413–425 | Cite as

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

  • Tsung-Chih Tseng
  • Duen-Yi Huang
  • Liang-Chuan Lai
  • Haw Hwai
  • Yi-Wen Hsiao
  • Jyun-Pei Jhou
  • Eric Y. Chuang
  • Shiang-Jong Tzeng
Original Article

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.

Keywords

7-Benzylidenenaltrexone (BNTX) Lupus nephritis FcγRIIB B cells Heme oxygenase-1 (HO-1) p38 MAPK 

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

109_2018_1626_Fig8_ESM.gif (22 kb)
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)

109_2018_1626_MOESM1_ESM.tiff (1.4 mb)
High resolution image (TIFF 1462 kb)
109_2018_1626_MOESM2_ESM.pdf (446 kb)
(PDF 445 kb)

References

  1. 1.
    Al-Hashimi M, Scott SW, Thompson JP, Lambert DG (2013) Opioids and immune modulation: more questions than answers. Br J Anaesth 111:80–88CrossRefPubMedGoogle Scholar
  2. 2.
    Bidlack JM, Khimich M, Parkhill AL, Sumagin S, Sun B, Tipton CM (2006) Opioid receptors and signaling on cells from the immune system. J NeuroImmune Pharmacol 1:260–269CrossRefPubMedGoogle Scholar
  3. 3.
    Zaki PA, Bilsky EJ, Vanderah TW, Lai J, Evans CJ, Porreca F (1996) Opioid receptor types and subtypes: the delta receptor as a model. Annu Rev Pharmacol Toxicol 36:379–401CrossRefPubMedGoogle Scholar
  4. 4.
    House RV, Thomas PT, Bhargava HN (1996) A comparative study of immunomodulation produced by in vitro exposure to delta opioid receptor agonist peptides. Peptides 17:75–81CrossRefPubMedGoogle Scholar
  5. 5.
    House RV, Thomas PT, Kozak JT, Bhargava HN (1995) Suppression of immune function by non-peptidic delta opioid receptor antagonists. Neurosci Lett 198:119–122CrossRefPubMedGoogle Scholar
  6. 6.
    Traynor JR, Elliott J (1993) Delta-opioid receptor subtypes and cross-talk with mu-receptors. Trends Pharmacol Sci 14:84–86CrossRefPubMedGoogle Scholar
  7. 7.
    Portoghese PS, Sultana M, Nagase H, Takemori AE (1992) A highly selective delta 1-opioid receptor antagonist: 7-benzylidenenaltrexone. Eur J Pharmacol 218:195–196CrossRefPubMedGoogle Scholar
  8. 8.
    Gavériaux-Ruff C, Filliol D, Simonin F, Matthes HW, Kieffer BL (2001) Immunosuppression by delta-opioid antagonist naltrindole: delta- and triple mu/delta/kappa-opioid receptor knockout mice reveal a nonopioid activity. J Pharmacol Exp Ther 298:1193–1198PubMedGoogle Scholar
  9. 9.
    Takahashi S, Fossati L, Iwamoto M, Merino R, Motta R, Kobayakawa T, Izui S (1996) Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest 97:1597–1604CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bagavant H, Fu SM (2009) Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol 21:489–494CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tzeng SJ (2016) The isolation, differentiation, and quantification of human antibody-secreting B cells from blood: ELISpot as a functional readout of humoral immunity. J Vis Exp (118).  https://doi.org/10.3791/54582
  12. 12.
    Shinnakasu R, Kurosaki T (2017) Regulation of memory B and plasma cell differentiation. Curr Opin Immunol 45:126–131CrossRefPubMedGoogle Scholar
  13. 13.
    Fukuyama H, Nimmerjahn F, Ravetch JV (2005) The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 6:99–106CrossRefPubMedGoogle Scholar
  14. 14.
    Xiang Z, Cutler AJ, Brownlie RJ, Fairfax K, Lawlor KE, Severinson E, Walker EU, Manz RA, Tarlinton DM, Smith KG (2007) FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol 8:419–429CrossRefPubMedGoogle Scholar
  15. 15.
    McGaha TL, Karlsson MC, Ravetch JV (2008) FcγRIIB deficiency leads to autoimmunity and a defective response to apoptosis in Mrl-MpJ mice. J Immunol 180:5670–5679CrossRefPubMedGoogle Scholar
  16. 16.
    Tzeng SJ, Li WY, Wang HY (2015) FcγRIIB mediates antigen-independent inhibition on human B lymphocytes through Btk and p38 MAPK. J Biomed Sci 22:87–98CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kie JH, Kapturczak MH, Traylor A, Agarwal A, Hill-Kapturczak N (2008) Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis. J Am Soc Nephrol 19:1681–1691CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Morimoto K, Ohta K, Yachie A, Yang Y, Shimizu M, Goto C, Toma T, Kasahara Y, Yokoyama H, Miyata T, Seki H, Koizumi S (2001) Cytoprotective role of heme oxygenase (HO)-1 in human kidney with various renal diseases. Kidney Int 60:1858–1866CrossRefPubMedGoogle Scholar
  19. 19.
    Almaani S, Meara A, Rovin BH (2017) Update on lupus nephritis. Clin J Am Soc Nephrol 12:825–835CrossRefPubMedGoogle Scholar
  20. 20.
    Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365:2110–2121CrossRefPubMedGoogle Scholar
  21. 21.
    Williams JP, Thompson JP, McDonald J, Barnes TA, Cote T, Rowbotham DJ, Lambert DG (2007) Human peripheral blood mononuclear cells express nociceptin/orphanin FQ, but not mu, delta, or kappa opioid receptors. Anesth Analg 105:998–1005CrossRefPubMedGoogle Scholar
  22. 22.
    Al-Hashimi M, McDonald J, Thompson JP, Lambert DG (2016) Evidence for nociceptin/orphanin FQ (NOP) but not μ (MOP), δ (DOP) or κ (KOP) opioid receptor mRNA in whole human blood. Br J Anaesth 116:423–429CrossRefPubMedGoogle Scholar
  23. 23.
    Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A (2011) Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 7:170–178CrossRefPubMedGoogle Scholar
  24. 24.
    Mumtaz IM, Hoyer BF, Panne D, Moser K, Winter O, Cheng QY, Yoshida T, Burmester GR, Radbruch A, Manz RA, Hiepe F (2012) Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: implications for the treatment of autoimmunity. J Autoimmun 39:180–188CrossRefPubMedGoogle Scholar
  25. 25.
    Hiepe F, Radbruch A (2016) Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol 12:232–240CrossRefPubMedGoogle Scholar
  26. 26.
    Mahévas M, Michel M, Weill JC, Reynaud CA (2013) Long-lived plasma cells in autoimmunity: lessons from B-cell depleting therapy. Front Immunol 4:494–498CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chan O, Shlomchik MJ (1998) A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 160:51–59PubMedGoogle Scholar
  28. 28.
    Chan OT, Madaio MP, Shlomchik MJ (1999) B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity. J Immunol 163:3592–3596PubMedGoogle Scholar
  29. 29.
    Tzeng SJ, Bolland S, Inabe K, Kurosaki T, Pierce SK (2005) The B cell inhibitory Fc receptor triggers apoptosis by a novel c-Abl family kinase-dependent pathway. J Biol Chem 280:35247–35254CrossRefPubMedGoogle Scholar
  30. 30.
    Kitamura M, Fine LG (1999) The concept of glomerular self-defense. Kidney Int 55:1639–1671CrossRefPubMedGoogle Scholar
  31. 31.
    Jarmi T, Agarwal A (2009) Heme oxygenase and renal disease. Curr Hypertens Rep 11:56–62CrossRefPubMedGoogle Scholar
  32. 32.
    Ohta K, Yachie A, Fujimoto K, Kaneda H, Wada T, Toma T, Seno A, Kasahara Y, Yokoyama H, Seki H, Koizumi S (2000) Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency. Am J Kidney Dis 35:863–870CrossRefPubMedGoogle Scholar
  33. 33.
    Chen X, Wei SY, Li JS, Zhang QF, Wang YX, Zhao SL, Yu J, Wang C, Qin Y, Wei QJ, Lv GX, Li B (2016) Overexpression of heme oxygenase-1 prevents renal interstitial inflammation and fibrosis induced by unilateral ureter obstruction. PLoS One 11:e0147084CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Takeda Y, Takeno M, Iwasaki M, Kobayashi H, Kirino Y, Ueda A, Nagahama K, Aoki I, Ishigatsubo Y (2004) Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibody. Clin Exp Immunol 138:237–244CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Elmarakby AA, Faulkner J, Baban B, Saleh MA, Sullivan JC (2012) Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats. Am J Physiol Renal Physiol 302:F791–F800CrossRefPubMedGoogle Scholar
  36. 36.
    Kamei J, Iwamoto Y, Suzuki T, Misawa M, Nagase H, Kasuya Y (1994) Involvement of delta 1-opioid receptor antagonism in the antitussive effect of δ-opioid receptor antagonists. Eur J Pharmacol 251:291–294CrossRefPubMedGoogle Scholar
  37. 37.
    Abdallah K, Gendron L (2017, 2017 May 17) The delta opioid receptor in pain control. Handb Exp Pharmacol.  https://doi.org/10.1007/164_2017_32
  38. 38.
    Gavériaux-Ruff C, Kieffer BL (2001) Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches. Behav Pharmacol 22:405–414CrossRefGoogle Scholar
  39. 39.
    Peppin JF, Raffa RB (2015) Delta opioid agonists: a concise update on potential therapeutic applications. J Clin Pharm Ther 40:155–166CrossRefPubMedGoogle Scholar
  40. 40.
    Nadal X, Baños JE, Kieffer BL, Maldonado R (2006) Neuropathic pain is enhanced in delta-opioid receptor knockout mice. Eur J Neurosci 23:830–834CrossRefPubMedGoogle Scholar
  41. 41.
    Gavériaux-Ruff C, Karchewski LA, Hever X, Matifas A, Kieffer BL (2008) Inflammatory pain is enhanced in delta opioid receptor-knockout mice. Eur J Neurosci 27:2558–2567CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Charbogne P, Kieffer BL, Befort K (2014) 15 years of genetic approaches in vivo for addiction research: opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76:204–217CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Tsung-Chih Tseng
    • 1
  • Duen-Yi Huang
    • 1
  • Liang-Chuan Lai
    • 2
    • 3
  • Haw Hwai
    • 1
  • Yi-Wen Hsiao
    • 3
  • Jyun-Pei Jhou
    • 1
  • Eric Y. Chuang
    • 3
    • 4
  • Shiang-Jong Tzeng
    • 1
  1. 1.Graduate Institute of PharmacologyNational Taiwan UniversityTaipeiTaiwan
  2. 2.Graduate Institute of PhysiologyNational Taiwan UniversityTaipeiTaiwan
  3. 3.Bioinformatics and Biostatistics Core, Center of Genomic MedicineCollege of Medicine, National Taiwan UniversityTaipeiTaiwan
  4. 4.Graduate Institute of Biomedical Electronics and BioinformaticsNational Taiwan UniversityTaipeiTaiwan

Personalised recommendations