Polydatin effectively attenuates disease activity in lupus-prone mouse models by blocking ROS-mediated NET formation

Springer Science and Business Media LLC - Tập 20 - Trang 1-11 - 2018
Pan Liao1,2, Yi He1,2, Fangyuan Yang1,2, Guihu Luo1,2, Jian Zhuang1,2, Zeqing Zhai1,2, Lili Zhuang1,2, Zhuomiao Lin3, Jiehuang Zheng3, Erwei Sun1,2
1Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
2Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, China
3School of Pharmaceutical Science, Southern Medical University, Guangzhou, China

Tóm tắt

Neutrophil extracellular trap (NET) formation has been described to be closely involved in the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the effect of polydatin (PD) on NET formation and its effects on disease activity in lupus-prone mouse models. In vitro, neutrophils from SLE patients and healthy people stimulated with phorbol 12-myristate 13-acetate (PMA) or phosphate-buffered saline (PBS) were treated with PD, and reactive oxygen species (ROS) production and NET formation examined. In vivo, pristane-induced lupus (PIL) mice were treated with vehicle, PD, mycophenolate mofetil (MMF) or cyclophosphamide (CYC) while MRL/lpr mice were treated with vehicle or PD. Proteinuria, serum autoantibodies, ROS production, NET formation and kidney histopathology were tested. Consistent with previous findings, blood neutrophils from SLE patients showed increased spontaneous NET formation. Both in vivo and in vitro, PD treatment significantly inhibited ROS production and NET release by neutrophils. In MRL/lpr mouse model, PD administration reduced the proteinuria, circulating autoantibody levels, and deposition of NETs and immune complex in the kidneys. In addition, PD treatment ameliorated lupus-like features in PIL mice as MMF or CYC did. PD treatment inhibited ROS-mediated NET formation and ameliorated lupus manifestations in both PIL mice and MRL/lpr mice. These results highlight the involvement of NETosis in SLE pathogenesis and reveal that PD might be a potential therapeutic agent for SLE or other autoimmune diseases.

Tài liệu tham khảo

Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–21. Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605–20. McMurray RW, May W. Sex hormones and systemic lupus erythematosus: review and meta-analysis. Arthritis Rheum. 2003;48(8):2100–10. Crispin JC, Kyttaris VC, Terhorst C, Tsokos GC. T cells as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6(6):317–25. Dorner T, Jacobi AM, Lee J, Lipsky PE. Abnormalities of B cell subsets in patients with systemic lupus erythematosus. J Immunol Methods. 2011;363(2):187–97. Crispin JC, Liossis SN, Kis-Toth K, Lieberman LA, Kyttaris VC, Juang YT, Tsokos GC. Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol Med. 2010;16(2):47–57. Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune WJ, Kaplan MJ. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. 2010;184(6):3284–97. Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M. New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation. Front Immunol. 2016;7:302. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187(1):538–52. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146–53. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A. 2010;107(21):9813–8. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3(73):20r–73r. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3(73):19r–73r. Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013;190(3):1217–26. Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, Gillespie BW, Carmona-Rivera C, Liu X, Subramanian V, et al. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheum. 2014;66(9):2532–44. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2015;74(7):1417–24. Pinegin B, Vorobjeva N, Pinegin V. Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. Autoimmun Rev. 2015;14(7):633–40. Patel S, Kumar S, Jyoti A, Srinag BS, Keshari RS, Saluja R, Verma A, Mitra K, Barthwal MK, Krishnamurthy H, et al. Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation. Nitric Oxide. 2010;22(3):226–34. Lai ZW, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, Miklossy G, Jimah J, Doherty E, Tily H, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64(9):2937–46. Qiao H, Chen H, Dong Y, Ma H, Zhao G, Tang F, Li Z. Polydatin attenuates H2O2-induced oxidative stress via PKC pathway. Oxidative Med Cell Longev. 2016;2016:5139458. Pang N, Chen T, Deng X, Chen N, Li R, Ren M, Li Y, Luo M, Hao H, Wu J, et al. Polydatin prevents methylglyoxal-induced apoptosis through reducing oxidative stress and improving mitochondrial function in human umbilical vein endothelial cells. Oxidative Med Cell Longev. 2017;2017:7180943. Cremon C, Stanghellini V, Barbaro MR, Cogliandro RF, Bellacosa L, Santos J, Vicario M, Pigrau M, Alonso CC, Lobo B, et al. Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome. Aliment Pharmacol Ther. 2017;45(7):909–22. Jiang KF, Zhao G, Deng GZ, Wu HC, Yin NN, Chen XY, Qiu CW, Peng XL. Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-kappaB pathway. Acta Pharmacol Sin. 2017;38(2):211–22. Li B, Wang XL. Effective treatment of polydatin weakens the symptoms of collagen-induced arthritis in mice through its anti-oxidative and anti-inflammatory effects and the activation of MMP-9. Mol Med Rep. 2016;14(6):5357–62. Jonsson CA, Svensson L, Carlsten H. Beneficial effect of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil on survival and severity of glomerulonephritis in systemic lupus erythematosus (SLE)-prone MRLlpr/lpr mice. Clin Exp Immunol. 1999;116(3):534–41. Jonsson CA, Erlandsson M, Svensson L, Molne J, Carlsten H. Mycophenolate mofetil ameliorates perivascular T lymphocyte inflammation and reduces the double-negative T cell population in SLE-prone MRLlpr/lpr mice. Cell Immunol. 1999;197(2):136–44. Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, Monestier M, Toy P, Werb Z, Looney MR. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122(7):2661–71. Austin HR, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 1984;25(4):689–95. Zhao J, Wang H, Dai C, Wang H, Zhang H, Huang Y, Wang S, Gaskin F, Yang N, Fu SM. P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum. 2013;65(12):3176–85. Sun E. Cell death recognition model for the immune system. Med Hypotheses. 2008;70(3):585–96. Sun EW, Shi YF. Apoptosis: the quiet death silences the immune system. Pharmacol Ther. 2001;92(2–3):135–45. Knight JS, Zhao W, Luo W, Subramanian V, O'Dell AA, Yalavarthi S, Hodgin JB, Eitzman DT, Thompson PR, Kaplan MJ. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123(7):2981–93. Knight JS, Subramanian V, O'Dell AA, Yalavarthi S, Zhao W, Smith CK, Hodgin JB, Thompson PR, Kaplan MJ. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2015;74(12):2199–206. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, Abdalrahman Z, Sciume G, Tsai WL, Trier AM, et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheum. 2017;69(1):148–60. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–87. Ling Y, Chen G, Deng Y, Tang H, Ling L, Zhou X, Song X, Yang P, Liu Y, Li Z, et al. Polydatin post-treatment alleviates myocardial ischaemia/reperfusion injury by promoting autophagic flux. Clin Sci (Lond). 2016;130(18):1641–53. Ni Z, Tao L, Xiaohui X, Zelin Z, Jiangang L, Zhao S, Weikang H, Hongchao X, Qiujing W, Xin L. Polydatin impairs mitochondria fitness and ameliorates podocyte injury by suppressing Drp1 expression. J Cell Physiol. 2017;232(10):2776–87. Du Y, Sanam S, Kate K, Mohan C. Animal models of lupus and lupus nephritis. Curr Pharm Des. 2015;21(18):2320–49. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178):140r–78r. Wang W, Peng W, Ning X. Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis. Int J Rheum Dis. 2018;21(2):415–21.