Deficiency of β-arrestin2 exacerbates inflammatory arthritis by facilitating plasma cell formation

Abstract

β-arrestin2 (β-arr2) is, a key protein that mediates desensitization and internalization of G protein-coupled receptors and participates in inflammatory and immune responses. Deficiency of β-arr2 has been found to exacerbate collagen antibody-induced arthritis (CAIA) through unclear mechanisms. In this study we tried to elucidate the molecular mechanisms underlying β-arr2 depletion-induced exacerbation of CAIA. CAIA was induced in β-arr2−/− and wild-type (WT) mice by injection of collagen antibodies and LPS. The mice were sacrificed on d 13 after the injection, spleen, thymus and left ankle joints were collected for analysis. Arthritis index (AI) was evaluated every day or every 2 days. We showed that β-arr2−/− mice with CAIA had a further increase in the percentage of plasma cells in spleen as compared with WT mice with CAIA, which was in accordance with elevated serum IgG1 and IgG2A expression and aggravating clinical performances, pathologic changes in joints and spleen, joint effusion, and joint blood flow. Both LPS stimulation of isolated B lymphocytes in vitro and TNP-LPS challenge in vivo led to significantly higher plasma cell formation and antibodies production in β-arr2−/− mice as compared with WT mice. LPS treatment induced membrane distribution of toll-like receptor 4 (TLR4) on B lymphocytes, accordingly promoted the nuclear translocation of NF-κB and the transcription of Blimp1. Immunofluorescence analysis confirmed that more TLR4 colocalized with β-arr2 in B lymphocytes in response to LPS stimulation. Depletion of β-arr2 restrained TLR4 on B lymphocyte membrane after LPS treatment and further enhanced downstream NF-κB signaling leading to additional increment in plasma cell formation. In summary, β-arr2 depletion exacerbates CAIA and further increases plasma cell differentiation and antibody production through inhibiting TLR4 endocytosis and aggravating NF-κB signaling.

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Fig. 1: β-arr2 depletion exacerbates CAIA in mice.
Fig. 2: β-arr2 depletion further increases plasma cell differentiation and antibody production in mice with CAIA.
Fig. 3: β-arr2 depletion enhances TLR4-mediated signaling in B lymphocytes of mice with CAIA.
Fig. 4: Loss of β-arr2 aggravates the TNP-LPS-induced humoral response in vivo.
Fig. 5: β-arr2 deficiency facilitates LPS-induced B lymphocyte activation, differentiation, and antibody production.
Fig. 6: Depletion of β-arr2 retains TLR4 on the plasma membrane and facilitates downstream NF-κB signaling in B lymphocytes.

References

  1. 1.

    Wang QT, Wang LS, Wu L, Zhang M, Hu SS, Wang R, et al. Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis. Sci Rep. 2017;7:e45364.

    Article  Google Scholar 

  2. 2.

    Han L, Zhang XZ, Wang C, Tang XY, Zhu Y, Cai XY, et al. IgD-Fc-Ig fusion protein, a new biological agent, inhibits T cell function in CIA rats by inhibiting IgD-IgDR-Lck-NF-kappaB signaling pathways. Acta Pharmacol Sin. 2020;41:800–12.

    CAS  Article  Google Scholar 

  3. 3.

    Fert-Bober J, Darrah E, Andrade F. Insights into the study and origin of the citrullinome in rheumatoid arthritis. Immunol Rev. 2020;294:133–47.

    CAS  Article  Google Scholar 

  4. 4.

    Volkov M, van Schie KA, van der Woude D. Autoantibodies and B cells: the ABC of rheumatoid arthritis pathophysiology. Immunol Rev. 2020;294:148–63.

    CAS  Article  Google Scholar 

  5. 5.

    Shu JL, Zhang XZ, Han L, Zhang F, Wu YJ, Tang XY, et al. Paeoniflorin-6’-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-kappaB signaling: comparison with biological agents. Acta Pharmacol Sin. 2019;40:801–13.

    CAS  Article  Google Scholar 

  6. 6.

    Wang QT, Ma Y, Liu DD, Zhang LL, Wei W. The roles of B cells and their interactions with fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis. Int Arch Allergy Immunol. 2011;155:205–11.

    CAS  Article  Google Scholar 

  7. 7.

    Meffre E, O’Connor KC. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol Rev. 2019;292:90–101.

    CAS  Article  Google Scholar 

  8. 8.

    Hwang IY, Park C, Harrison K, Kehrl JH. TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones. J Exp Med. 2009;206:2641–57.

    CAS  Article  Google Scholar 

  9. 9.

    Dekkers JS, Schoones JW, Huizinga TW, Toes RE, van der Helm-van Mil AH. Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: a systematic literature review and meta-analysis. Ann Rheum Dis. 2017;76:458–67.

    CAS  Article  Google Scholar 

  10. 10.

    Liu G, Lu Y, Shi L, Ren Y, Kong J, Zhang MY, et al. TLR4-MyD88 signaling pathway is responsible for acute lung inflammation induced by reclaimed water. J Hazard Mater. 2020;396:e122586.

    Article  Google Scholar 

  11. 11.

    Rajaiah R, Perkins DJ, Ireland DD, Vogel SN. CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance. Proc Natl Acad Sci USA. 2015;112:8391–6.

    CAS  Article  Google Scholar 

  12. 12.

    Wang R, Zhang M, Hu SS, Liu KK, Tai Y, Tao J, et al. Ginsenoside metabolite compound-K regulates macrophage function through inhibition of beta-arrestin2. Biomed Pharmacother. 2019;115:e108909.

    Article  Google Scholar 

  13. 13.

    Sun S, Cao H, Yao N, Zhao L, Zhu X, Ni EA, et al. Beta-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-kappaB signal pathway in murine hearts. Acta Pharmacol Sin. 2020;41:198–207.

    CAS  Article  Google Scholar 

  14. 14.

    Alexander RA, Lot I, Enslen H. Methods to characterize protein interactions with beta-arrestin in cellulo. Methods Mol Biol. 2019;1957:139–58.

    CAS  Article  Google Scholar 

  15. 15.

    Wang QT, Zhang LL, Wu HX, Wei W. The expression change of beta-arrestins in fibroblast-like synoviocytes from rats with collagen-induced arthritis and the effect of total glucosides of paeony. J Ethnopharmacol. 2011;133:511–6.

    CAS  Article  Google Scholar 

  16. 16.

    Li H, Smalligan DA, Xie N, Javer A, Zhang Y, Hanley G, et al. Beta-arrestin 2-mediated immune suppression induced by chronic stress. Neuroimmunomodulation. 2011;18:142–9.

    CAS  Article  Google Scholar 

  17. 17.

    Li P, Cook JA, Gilkeson GS, Luttrell LM, Wang L, Borg KT, et al. Increased expression of beta-arrestin1 and 2 in murine models of rheumatoid arthritis: isoform specific regulation of inflammation. Mol Immunol. 2011;49:64–74.

    Article  Google Scholar 

  18. 18.

    Fernandez-Zafra T, Gao T, Jurczak A, Sandor K, Hore Z, Agalave NM, et al. Exploring the transcriptome of resident spinal microglia after collagen antibody-induced arthritis. Pain. 2019;160:224–36.

    CAS  Article  Google Scholar 

  19. 19.

    Liu KK, Wang Q, Yang SM, Chen J, Wu HX, Wei W. Ginsenoside compound K suppresses the abnormal activation of T lymphocytes in mice with collagen-induced arthritis. Acta Pharmacol Sin. 2014;35:599–612.

    CAS  Article  Google Scholar 

  20. 20.

    Clavel G, Marchiol-Fournigault C, Renault G, Boissier MC, Fradelizi D, Bessis N. Ultrasound and Doppler micro-imaging in a model of rheumatoid arthritis in mice. Ann Rheum Dis. 2008;67:1765–72.

    CAS  Article  Google Scholar 

  21. 21.

    Huang B, Wang Q, Song S, Wu YJ, Ma Y, Zhang LL, et al. Combined use of etanercept and MTX restores CD4+/CD8+ ratio and Tregs in spleen and thymus in collagen-induced arthritis. Inflamm Res. 2012;61:1229–39.

    CAS  Article  Google Scholar 

  22. 22.

    Rui L, Healy JI, Blasioli J, Goodnow CC. ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation. J Immunol. 2006;177:5337–46.

    CAS  Article  Google Scholar 

  23. 23.

    Turner VM, Mabbott NA. Ageing adversely affects the migration and function of marginal zone B cells. Immunology. 2017;151:349–62.

    CAS  Article  Google Scholar 

  24. 24.

    Wang J, Liu SC, Hou BD, Yang MX, Dong ZJ, Qi H, et al. PTEN-regulated AID transcription in germinal center B cells is essential for the class-switch recombination and IgG antibody responses. Front Immunol. 2018;9:e371.

    Article  Google Scholar 

  25. 25.

    Leibler C, Thiolat A, Henique C, Samson C, Pilon C, Tamagne M, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk. J Am Soc Nephrol. 2018;29:1049–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Wang QT, Wu YJ, Huang B, Ma Y, Song S, Zhang LL, et al. Etanercept attenuates collagen-induced arthritis by modulating the association between BAFFR expression and the production of splenic memory B cells. Pharmacol Res. 2013;68:38–45.

    CAS  Article  Google Scholar 

  27. 27.

    Derksen V, Huizinga T, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017;39:437–46.

    CAS  Article  Google Scholar 

  28. 28.

    Lewis MJ, Barnes MR, Blighe K, Goldmann K, Rana S, Hackney JA, et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 2019;28:2455–70.

    CAS  Article  Google Scholar 

  29. 29.

    Shah M, Kim GY, Achek A, Cho EY, Baek WY, Choi YS, et al. The alphaC helix of TIRAP holds therapeutic potential in TLR-mediated autoimmune diseases. Biomaterials. 2020;245:e119974.

    Article  Google Scholar 

  30. 30.

    Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell. 2011;147:868–80.

    CAS  Article  Google Scholar 

  31. 31.

    Pascual-Lucas M, Fernandez-Lizarbe S, Montesinos J, Guerri C. LPS or ethanol triggers clathrin- and rafts/caveolae-dependent endocytosis of TLR4 in cortical astrocytes. J Neurochem. 2014;129:448–62.

    CAS  Article  Google Scholar 

  32. 32.

    Sharma D, Malik A, Steury MD, Lucas PC, Parameswaran N. Protective role of beta-arrestin2 in colitis through modulation of T-cell activation. Inflamm Bowel Dis. 2015;21:2766–77.

    Article  Google Scholar 

  33. 33.

    Feng X, Wu C, Burton FH, Loh HH, Wei L. Beta-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. Cell Death Differ. 2014;21:397–406.

    CAS  Article  Google Scholar 

  34. 34.

    Sharma D, Parameswaran N. Multifaceted role of beta-arrestins in inflammation and disease. Genes Immun. 2015;16:e576.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81202541, 81973332, 81973314), the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars (1808085J28), the Key Projects of Natural Science Research of Anhui Colleges and Universities (KJ2017A176), Anhui University Excellent Youth Talent Support Program (gxyqZD2017025), Innovation and Entrepreneurship Support Program for Returnees of Anhui Province, the Foundation for Young Academic Backbone of Anhui Medical University, and the Grants for Young Talents of Anhui Medical University (2013).

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WJZ, DDW, JT, YT, ZWZ, ZW, PPG, WYS, JYC, HXW, SXY and LLZ conducted the study and analyzed the data, WJZ, QTW and WW analyzed the data and wrote the paper.

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Correspondence to Qing-tong Wang or Wei Wei.

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The authors declare no competing interests.

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Zhou, Wj., Wang, Dd., Tao, J. et al. Deficiency of β-arrestin2 exacerbates inflammatory arthritis by facilitating plasma cell formation. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-00507-1

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Keywords

  • rheumatoid arthritis
  • β-arrestin2
  • TLR4
  • plasma cell
  • B lymphocytes
  • LPS

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