Aspirin alleviates the symptoms of immunoglobulin A nephropathy via suppressing platelets-mediated non-canonical NF-κB activation in B cells
Abstract
Purpose: Antiplatelet aggregation drugs, such as aspirin, can alleviate pathological renal damage in immunoglobulin A (IgA) nephropathy, although the precise mechanism is unclear.
Methods: The serum levels of platelet factor 4 (PF4), IgA, and platelet-activating factor (PAF) were assessed by enzyme-linked immunosorbent assay in IgA nephropathy patients and TANK-binding kinase 1 (TBK1)-/- tumor necrosis factor (TNF)-/- mice. The deposition of IgA in glomeruli was detected by immunofluorescence. Phorbol-12-myristate-13-acetate (PMA) induced platelets activation was examined by the cell counting kit 8 assay. B cells were further stimulated with lipopolysaccharides (LPS) or plus platelets supernatant, or combined with nuclear factor kappa-B (NF-κB) inducing kinase (NIK) inhibitor, NIK SMI1.
Results: Increased serum IgA and proportion of activated platelets were observed in IgA nephropathy patients. TBK1-/-TNF-/- mice had significant increased urinary protein and serum creatinine, and IgA deposition in glomeruli. Up-regulated serum PF4 and PAF were observed in both the IgA nephropathy patients and TBK1-/-TNF-/- mice. Aspirin suppressed the deposition of IgA in glomeruli of TBK1-/-TNF-/- mice with down-regulated platelets activation. Platelets supernatant could promote the proliferation of B cells with up-regulated IgA and sCD40L secretion and up-regulated P52 and RelB expression, which could be inhibited by NIK SMI1 administration.
Conclusion: TBK1-/-TNF-/- mice demonstrate IgA nephropathy phenotype, which could be alleviated by aspirin administration via inhibiting platelets induced non-canonical NF-κB activation mediated IgA production in B cells.
Downloads
References
Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nat Rev Dis Primers 2016; 2: 16001. doi: 10.1038/nrdp.2016.1
Floege J, Amann K. Primary glomerulonephritides. Lancet 2016; 387(10032): 2036–48. doi: 10.1016/S0140-6736(16)00272-5
Floege J, Feehally J. Treatment of IgA nephropathy and Henoch-Schönlein nephritis. Nat Rev Nephrol 2013; 9(6): 320–7. doi: 10.1038/nrneph.2013.59
Liu XJ, Geng YQ, Xin SN, Huang GM, Tu XW, Ding ZR, et al. Antithrombotic drug therapy for IgA nephropathy: a meta analysis of randomized controlled trials. Intern Med 2011; 50(21): 2503–10. doi: 10.2169/internalmedicine.50.5971
Taji Y, Kuwahara T, Shikata S, Morimoto T. Meta-analysis of antiplatelet therapy for IgA nephropathy. Clin Exp Nephrol 2006; 10(4): 268–73. doi: 10.1007/s10157-006-0433-8
Hale GM, McIntosh SL, Hiki Y, Clarkson AR, Woodroffe AJ. Evidence for IgA-specific B cell hyperactivity in patients with IgA nephropathy. Kidney Int 1986; 29(3): 718–24. doi: 10.1038/ki.1986.57
Chang D, Cheng Y, Luo R, Zhang C, Zuo M, Xu Y, et al. The prognostic value of platelet-to-lymphocyte ratio on the long-term renal survival in patients with IgA nephropathy. Int Urol Nephrol 2021; 53(3): 523–30. doi: 10.1007/s11255-020-02651-3
Tomino Y, Tsushima Y, Ohmuro H, Shimizu M, Kuramoto T, Shirato I, et al. Detection of activated platelets in urinary sediments by immunofluorescence using monoclonal antibody to human platelet GMP-140 in patients with IgA nephropathy. J Clin Lab Anal 1993; 7(6): 329–33. doi: 10.1002/jcla.1860070606
Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2002; 2(7): 465–75. doi: 10.1038/nri844
Cazac BB, Roes J. TGF-β receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 2000; 13(4): 443–51. doi: 10.1016/S1074-7613(00)00044-3
Jin J, Xiao Y, Chang JH, Yu J, Hu H, Starr R, et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling. Nat Immunol 2012; 13(11): 1101–9. doi: 10.1038/ni.2423
Zamora C, Cantó E, Vidal S. The dual role of platelets in the cardiovascular risk of chronic inflammation. Front Immunol 2021; 12: 625181. doi: 10.3389/fimmu.2021.625181
Aukrust P, Müller F, Ueland T, Berget T, Aaser E, Brunsvig A, et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100(6): 614–20. doi: 10.1161/01.CIR.100.6.614
Chaturvedi R, Gupta M, Jain A, Das T, Prashar S. Soluble CD40 ligand: a novel biomarker in the pathogenesis of periodontal disease. Clin Oral Investig 2015; 19(1): 45–52. doi: 10.1007/s00784-014-1216-3
Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in autoimmune diseases: humoral immunity and beyond. Adv Drug Deliv Rev 2019; 141: 92–103. doi: 10.1016/j.addr.2018.12.005
Wykes M. Why do B cells produce CD40 ligand? Immunol Cell Biol 2003; 81(4): 328–31. doi: 10.1046/j.1440-1711.2003.01171.x
Doublier S, Zennaro C, Musante L, Spatola T, Candiano G, Bruschi M, et al. Soluble CD40 ligand directly alters glomerular permeability and may act as a circulating permeability factor in FSGS. PLoS One 2017; 12(11): e0188045. doi: 10.1371/journal.pone.0188045
Lamine LB, Turki A, Al-Khateeb G, Sellami N, Amor HB, Sarray S, et al. Elevation in circulating soluble CD40 ligand concentrations in type 2 diabetic retinopathy and association with its severity. Exp Clin Endocrinol Diabetes 2020; 128(5): 319–24. doi: 10.1055/a-0647-6860
Prasad KS, Andre P, He M, Bao M, Manganello J, Phillips DR. Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci U S A 2003; 100(21): 12367–71. doi: 10.1073/pnas.2032886100
Field DJ, Aggrey-Amable AA, Blick SK, Ture SK, Johanson A, Cameron SJ, et al. Platelet factor 4 increases bone marrow B cell development and differentiation. Immunol Res 2017; 65(5): 1089–94. doi: 10.1007/s12026-017-8951-x
Smith CS, Parker L, Shearer WT. Cytokine regulation by platelet-activating factor in a human B cell line. J Immunol 1994; 153(9): 3997–4005. doi: 10.4049/jimmunol.153.9.3997
Nguer CM, Pellegrini O, Galanaud P, Benveniste J, Thomas Y, Richard Y. Regulation of paf-acether receptor expression in human B cells. J Immunol 1992; 149(8): 2742–8. doi: 10.4049/jimmunol.149.8.2742
Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 2017; 17(9): 545–58. doi: 10.1038/nri.2017.52
Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 2018; 18(5): 309–24. doi: 10.1038/nri.2017.142
Zhao B, Barrera Luis A, Ersing I, Willox B, Schmidt Stefanie CS, Greenfeld H, et al. The NF-κB genomic landscape in lymphoblastoid B cells. Cell Rep 2014; 8(5): 1595–606. doi: 10.1016/j.celrep.2014.07.037
Sasaki Y, Iwai K. Roles of the NF-κB pathway in B-lymphocyte biology. Curr Top Microbiol Immunol 2016; 393: 177–209. doi: 10.1007/82_2015_479
Copyright (c) 2023 Priyanka Maunga, Nomvula Johannes
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain full copyright to their individual works, and publishing rights without restrictions.
In accordance with the Budapest Open Access Initiative, articles published in STEMedicine are freely available "on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited."
Except where otherwise noted, all content on this website is licensed under a Creative Commons Attribution 4.0 License. This license allows for commercial and non-commercial redistribution as well as modifications of the work as long as attribution is given to the authors and STEMedicine as the original publication source, and a link to the article on the STEMedicine website is provided.