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Knockdown of RSAD2 attenuates B cell hyperactivity in patients with primary Sjögren’s syndrome (pSS) via suppressing NF-κb signaling pathway

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Abstract

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is mainly characterized as abnormal activation of B cells. It is reported that radical s-adenosyl methionine domain-containing 2 (RSAD2) is overexpressed in CD19+ B cells of pSS patients, but its role in pSS B cells remains unknown. Herein, RSAD2 expression was upregulated in CD19+ B cells of pSS patients and positively correlated with the expression of interleukin-10 (IL-10) in serum. After CD40L stimulation, knockdown of RSAD2 significantly attenuated cell viability, the production levels of immunoglobins and the expression of IL-10, while promoted cell apoptosis of pSS CD19+ B cells. Mechanistically, knockdown of RSAD2 negatively regulated nuclear factor kappa-b (NF-κb) signaling pathway. In addition, overexpression of p65 prominently alleviated the inhibitory effect of RSAD2 knockdown on proliferation, immunoglobin production and IL-10 expression in CD40L-induced CD19+ B cells. Our study indicated that silencing RSAD2 attenuated pSS B cell hyperactivity via suppressing NF-κb signaling pathway, which might provide a potential therapeutic target for pSS treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Mariette X, Criswell LA (2018) Primary Sjögren’s syndrome. N Engl J Med 378(10):931–939. https://doi.org/10.1056/NEJMc1804598

    Article  PubMed  Google Scholar 

  2. Liu Z, Yang X, Tian Z, Qian J, Wang Q, Zhao J, Huang C, Liu Y, Guo X, Wang H (2018) The prognosis of pulmonary arterial hypertension associated with primary Sjögren’s syndrome: a cohort study. Lupus 27(7):1072–1080

    Article  CAS  Google Scholar 

  3. Xiuhong W, Yi L, Shun C, Bo C (2018) The role of RORα in salivary gland lesions in patients with primary Sjgren’s syndrome

  4. Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl K, Kelly JA, Dozmorov MG, Micelirichard C, Bowman SJ (2013) Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome. Nat Genet 45(11):1284–1294

    Article  CAS  Google Scholar 

  5. Wang-Renault S-F, Boudaoud S, Nocturne G, Roche E, Sigrist N (2018) Deregulation of microRNA expression in purified T and B lymphocytes from patients with primary Sjogren’s syndrome. Ann Rheumatic Diseases J Clin Rheumatol Connect Tissue Res

  6. Nocturne G, Mariette X (2018) B cells in the pathogenesis of primary Sjogren syndrome. Nat Rev Rheumatol

  7. Guo J, Gu M, Zhang W, Liu Y, Deng A (2018) Aberrant IL-35 levels in patients with primary Sjogren’s syndrome. Scand J Immunol 88(5):e12718

    Article  Google Scholar 

  8. Letaief H, Lukas C, Barnetche T, Gaujoux-Viala C, Combe B, Morel J (2018) Efficacy and safety of biological DMARDs modulating B cells in primary Sjgren’s syndrome: systematic review and meta-analysis. Joint Bone Spine:S1297319X17301318

  9. Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, Mauri C (2013) CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Ence Trans Med 5(173):173ra123

    Google Scholar 

  10. Ben-Eli H, Gomel N, Aframian DJ, Abu-Seir R, Perlman R, Ben-Chetrit E, Mevorach D, Kleinstern G, Paltiel O, Solomon A (2019) SNP variations in IL10, TNFα and TNFAIP3 genes in patients with dry eye syndrome and Sjogren’s syndrome. J Inflam (London, England) 16:6. https://doi.org/10.1186/s12950-019-0209-z

    Article  Google Scholar 

  11. Lin X, Wang X, Xiao F, Ma K, Liu L, Wang X, Xu D, Wang F, Shi X, Liu D, Zhao Y, Lu L (2019) IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjögren’s syndrome. Cell Mol Immunol 16(12):921–931. https://doi.org/10.1038/s41423-019-0227-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ebrahimi KH, Vowles J, Browne C, Mccullagh JSO, James W (2020) Viperin (RSAD2) radical log AM activity is a metabolic regulator of antiviral immunity

  13. Yogarajah T, Ong KC, Perera D, Thong Wong K (2018) RSAD2 and AIM2 modulate Coxsackievirus A16 and Enterovirus A71 replication in neuronal cells in different ways that may be associated with their 5’ nontranslated regions. J Virol: JVI:01914–01917

  14. Matz M, Heinrich F, Zhang Q, Lorkowski C, Seelow E, Wu K, Lachmann N, Addo RK, Durek P, Mashreghi M-F (2018) The regulation of IFN type I pathway related genes RSAD2 and ETV7 specifically indicate antibody-mediated rejection after kidney transplantation. Clin Transpl

  15. Stancy J, Nysia G, Bridgett G-K, Edward T (2018) Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI. J Autoimmun

  16. Raterman HG, Vosslamber S, Ridder SD, Nurmohamed MT, Voskuyl AE (2012) The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther 14(2):R95–R95

    Article  CAS  Google Scholar 

  17. Fan H, Zhao G, Ren D, Liu F, Dong G, Hou Y (2016) Gender differences of B cell signature related to estrogen-induced IFI44L/BAFF in systemic lupus erythematosus. Immunol Lett 181(Complete):71–78

    PubMed  Google Scholar 

  18. Ramos PS, Zimmerman K, Haddad S, Langefeld CD, Medsger TA, Feghalibostwick CA (2019) Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets. Clin Epigenetics 11(1):58

    Article  Google Scholar 

  19. H-z Z, S-y L, C-f L, Z-l C, T-h S, L-l Z, He C-m, Wang M, Zhang W, Zhang F-C (2020) Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjögren’s syndrome. Ann Rheum Dis

  20. Bodewes ILA, Björk A, Versnel MA, Wahren-Herlenius M (2019) Innate immunity and interferons in the pathogenesis of Sjögren’s syndrome. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/key360

  21. Bjork A, Andersson ER, Imgenbergkreuz J, Thorlacius GE, Mofors J, Syvanen A, Kvarnstrom M, Nordmark G, Wahrenherlenius M (2020) Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren’s syndrome. RMD Open 6(1)

  22. Inamo J, Suzuki K, Takeshita M, Kassai Y, Takiguchi M, Kurisu R, Okuzono Y, Tasaki S, Yoshimura A, Takeuchi T (2020) Identification of novel genes associated with dysregulation of B cells in patients with primary Sjögren’s syndrome. Arthritis Res Ther 22(1):153. https://doi.org/10.1186/s13075-020-02248-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin T, Walker G, Kurji K, Fang E, Law G, Prasad SS, Kojic L, Cao S, White VA, Cui JZ (2013) Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye. Cytokine 62(3):369–381

    Article  CAS  Google Scholar 

  24. Nilsson AM, Tufvesson E, Hesselstrand R, Olsson P, Wollmer P, Mandl T (2019) Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sjögren’s syndrome patients. Scand J Rheumatol 48(2):149–156. https://doi.org/10.1080/03009742.2018.1473488

    Article  CAS  PubMed  Google Scholar 

  25. Mavragani CP, Crow MK (2010) Activation of the type I interferon pathway in primary Sjogren’s syndrome. J Autoimmun 35(3):225–231

    Article  CAS  Google Scholar 

  26. Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C, Padyukov L, Truedsson L, Alm GV, Eloranta M (2009) Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogren’s syndrome. Genes Immun 10(1):68–76

    Article  CAS  Google Scholar 

  27. Agnès Doreau AB, Bastid J, Riche B, Trescol-Biemont M-C, Ranchin B, Fabien N, Cochat P, Pouteil-Noble C, Trolliet P, Durieu I, Tebib J, Kassai B, Ansieau S, Puisieux A, Eliaou J-F, Bonnefoy-Bérard N (2014) Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 15(9):894

    Article  Google Scholar 

  28. Ji-Su J, Jun-Ho L, Nam-Chul J, So-Yeon C, Soo-Yeoun P, Ji-Young Y, Song JY, Geuk SH, Soo LH, Dae-Seog L (2018) Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway. Cell Death Dis 9(8):823

    Article  Google Scholar 

  29. Aristides Moschonas MI, Aristides G Eliopoulos (2012) CD40 stimulates a “feed-forward” NF-κB-driven molecular pathway that regulates IFN-β expression in carcinoma cells. J Immunol 188(11):5521–5527

    Article  Google Scholar 

  30. Tanya S, Artem V, Sadik CD, Detlef Z, Yask G, Ludwig RJ (2017) Gene expression analysis reveals novel shared gene signatures and candidate molecular mechanisms between pemphigus and systemic lupus erythematosus in CD4+ T cells. Front Immunol 8:1992

    Google Scholar 

  31. Qiu L, Cresswell P, Chin K (2009) Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1. Blood 113(15):3520–3529

    Article  CAS  Google Scholar 

  32. Zhenglu X, Yang W, Juqing H, Ning Q, Guozhi S (2019) Anti-inflammatory activity of polysaccharides from Phellinus linteus by regulating the NF-κB translocation in LPS-stimulated RAW264.7 macrophages. Int J Biol Macromol

  33. Ping, Meng, Zhuang-Gui, Chen, Tian-Tuo, Zhang, Zhuo-Zheng, Liang, Xiao-Ling, Zou (2018) IL-37 alleviates house dust mite-induced chronic allergic asthma by targeting TSLP through the NF-κB & ERK1/2 signaling pathways. Immunol Cell Biol

  34. Grondona P, Bucher P, Schulze-Osthoff K, Hailfinger S, Schmitt A (2018) NF-κB activation in lymphoid malignancies: genetics, signaling, and targeted therapy. Biomedicines 6(2):38

    Article  Google Scholar 

  35. Wang X, Shaalan A, Liefers S, Coudenys J, Elewaut D, Proctor GB, Bootsma H, Kroese FGM, Pringle S (2018) Dysregulation of NF-kB in glandular epithelial cells results in Sjgren’s-like features. PLoS One 13(8)

  36. Lisi S, Sisto M, Lofrumento DD, D’Amore M (2012) Altered IκBα expression promotes NF-κB activation in monocytes from primary Sjögren’s syndrome patients. Pathology 44(6):557

    Article  CAS  Google Scholar 

  37. Li P, Yang Y, Jin Y, Zhao R, Gu Z (2019) B7-H3 participates in human salivary gland epithelial cells apoptosis through NF-κB pathway in primary Sjgren’s syndrome. J Transl Med 17(1)

  38. Pontoriero M, Fiume G, Vecchio E, de Laurentiis A, Albano F, Iaccino E, Mimmi S, Pisano A, Agosti V, Giovannone E, Altobelli A, Caiazza C, Mallardo M, Scala G, Quinto I (2019) Activation of NF-κB in B cell receptor signaling through Bruton’s tyrosine kinase-dependent phosphorylation of IκB-α. J Mol Med (Berl) 97(5):675–690. https://doi.org/10.1007/s00109-019-01777-x

    Article  CAS  Google Scholar 

  39. H-z Z, S-y L, C-f L, Z-l C, T-h S, L-l Z, He C-m, Wang M, Zhang W, F-c Z (2020) Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjögren’s syndrome. Ann Rheum Dis 79(4):518–524

    Article  Google Scholar 

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  1. Hong Zhu and Jian Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, General Hospital of Ningxia Medical University, No. 804 Sheng Li Street, XingQing District, Yinchuan City, 750004, Ningxia Hui Autonomous Region, China

    Hong Zhu, Jian Zheng, Yan Zhou, Tong Wu & Tiantian Zhu

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  1. Hong Zhu
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  2. Jian Zheng
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  3. Yan Zhou
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  4. Tong Wu
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Correspondence to Jian Zheng.

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This study was approved by the ethics committee of the General Hospital of Ningxia Medical University. Prior to participating in the study, each participant signed a written informed consent form. The study was conducted according to the principles of the Declaration of Helsinki.

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Zhu, H., Zheng, J., Zhou, Y. et al. Knockdown of RSAD2 attenuates B cell hyperactivity in patients with primary Sjögren’s syndrome (pSS) via suppressing NF-κb signaling pathway. Mol Cell Biochem 476, 2029–2037 (2021). https://doi.org/10.1007/s11010-021-04070-z

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