Mangiferin Promotes Bregs Level, Activates Nrf2 Antioxidant Signaling, and Inhibits Proinflammatory Cytokine Expression in Murine Splenic Mononuclear Cells In Vitro

Abstract

Recent studies indicated that regulatory B cells (Bregs) and nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway play important roles in the pathogenesis of chronic graft-versus-host disease (cGVHD). Mangiferin (MA), a polyphenol compound, has been reported to activate Nrf2/antioxidant-responsive element (ARE) signaling pathway. This study was aimed to investigate the effects of MA on Bregs and Nrf2 antioxidant signaling in murine splenic mononuclear cells (MNCs) in vitro. Our results revealed that MA could increase the Bregs level in murine splenic MNCs. Moreover, MA up-regulated the expression of Bregs-associated immunosuppressive factor interleukin-10 (IL-10) by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) signaling in murine splenic MNCs. Meanwhile, MA inhibited the proinflammatory cytokines IL-2 and interferon-γ (INF-γ) at both mRNA and protein levels. MA also enhanced the transcription and protein expression of Nrf2 and NADPH quinine oxidoreductase 1 (NQO1), whereas decreased that of Kelch-like ECH-associated protein 1 (Keap1) in murine splenic MNCs. Moreover, MA promoted the proliferation and inhibited the apoptosis of murine splenic MNCs. These results suggested that MA exerts immunosuppressive effects by upregulating the Bregs level, activating the Nrf2 antioxidant pathway, and inhibiting the expression of pro-immunoinflammatory factors. MA, as a natural immunomodulatory and anti-inflammatory agent, may have a potential role in the prophylaxis and treatment of cGVHD.

Keywords

mangiferin / regulatory B cells / nuclear factor erythroid 2-related factor 2 / interleukin-10 / immunomodulation / anti-inflammation

References

[1] LeeSJ. Classification systems for chronic graft-versushost disease. Blood, 2016, 129(1): 30-37

[2] CutlerCS, KorethJ, RitzJ. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood, 2017, 129(1): 22-29

[3] PreslandRB. Biology of chronic graft-vs -host disease: Immune mechanisms and progress in biomarker discovery. World J Transplant, 2016, 6(4): 608-619

[4] NakasoneH, SahafB, MiklosDB. Therapeutic benefits targeting B-cells in chronic graft-versus-host disease. Int J Hematol, 2015, 101(5): 438-451

[5] GreinixHT. Chronic GVHD: progress in salvage treatment. Blood, 2017, 130(21): 2237-2238

[6] SarantopoulosS, BlazarBR, CutlerC, et al.. Reprint of: B Cells in Chronic Graft-versus-Host Disease. Biol Blood Marrow TR, 2015, 21(2): S11-S18

[7] WangT, MeiY, LiZ. Research Progress on Regulatory B Cells in Systemic Lupus Erythematosus. Biomed Res Int, 2019, 2019: 1-7

[8] YuanC, LiX, LuoL, et al.. Mannose-capped lipoarabinomannan-induced B10 cells decrease severity of dextran sodium sulphate-induced inflammatory bowel disease in mice. Scand J Immunol, 2019, 91(2): e12843

[9] BankóZ, PozsgayJ, SziliD, et al.. Induction and Differentiation of IL-10-Producing Regulatory B Cells from Healthy Blood Donors and Rheumatoid Arthritis Patients. J Immunol, 2017, 198(4): 1512-1520

[10] Staun-RamE, MillerA. Effector and regulatory B cells in Multiple Sclerosis. Clin Immunol, 2017, 184: 11-25

[11] SarvariaA, BasarR, MehtaRS, et al.. IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation. Blood, 2016, 128(10): 1346-1361

[12] PengY, ChenX, LiuQ, et al.. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia, 2015, 29(3): 636-646

[13] SahaS, ButtariB, PanieriE, et al.. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules, 2020, 25(22): 5474

[14] MorettiD, TamboneS, CerretaniM, et al.. NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington’s disease mouse model. Free Radic Biol Med, 2021, 162: 243-254

[15] LimJ, HeoJ, JuH, et al.. Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway. Sci Adv, 2020, 6(16): a1334

[16] Jyotshna, KhareP, ShankerK. Mangiferin: A review of sources and interventions for biological activities. Biofactors, 2016, 42(5): 504-514

[17] DuS, LiuH, LeiT, et al.. Mangiferin: An effective therapeutic agent against several disorders (Review). Mol Med Rep, 2018, 18(6): 4775-4786

[18] SahaS, SadhukhanP, SilPC. Mangiferin: A xanthonoid with multipotent anti-inflammatory potential. BioFactors, 2016, 42(5): 459-474

[19] PanC, PanZ, HuJ, et al.. Mangiferin alleviates lipopolysaccharide and D-galactosamine-induced acute liver injury by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. Eur J Pharmacol, 2016, 770: 85-91

[20] SahaS, RashidK, SadhukhanP, et al.. Attenuative role of mangiferin in oxidative stress-mediated liver dysfunction in arsenic-intoxicated murines. BioFactors, 2016, 42(5): 515-532

[21] ZhangB, ZhaoJ, LiS, et al.. Mangiferin activates Nrf2-antioxidant response element signaling without reducing the sensitivity to etoposide of human myeloid leukemia cells in vitro. Acta Pharmacol. Sin, 2014, 35(2): 257-266

[22] ZhangB, ZhaoJ, LiS, et al.. Mangiferin activates the Nrf2-ARE pathway and reduces etoposide-induced DNA damage in human umbilical cord mononuclear blood cells. Pharm Biol, 2014, 53(4): 503-511

[23] KolupaevOV, DantTA, BommiasamyH, et al.. Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD. Blood Adv, 2018, 2(18): 2307-2319

[24] Le HuuD, MatsushitaT, JinG, et al.. Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease. Blood, 2013, 121(16): 3274-3283

[25] KangS, PingC, MengranL. The 46th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Poster Session (P001-P706). Bone Marrow Transpl, 2020, 55(S1): 181-714

[26] KhuranaRK, KaurR, LohanS, et al.. Mangiferin: a promising anticancer bioactive. Pharm Pat Anal, 2016, 5(3): 169-181

[27] CaiX, ZhangL, WeiW. Regulatory B cells in inflammatory diseases and tumor. Int Immunopharmacol, 2019, 67: 281-286

[28] de MassonA, SociéG, BagotM, et al.. Deficient regulatory B cells in human chronic graft-versus-host disease. Oncoimmunology, 2015, 4(7): e1016707

[29] AgrawalS, GollapudiS, SuH, et al.. Leptin activates human B cells to secrete TNF-alpha, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol, 2011, 31(3): 472-478

[30] WangZ, ChengQ, TangK, et al.. Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory B (Breg) cells. Cancer Lett, 2015, 364(2): 118-124

[31] PalR, ChaudharyMJ, TiwariPC, et al.. Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats. Inflammopharmacology, 2019, 27(2): 291-299

[32] ZniakVK, PaluszczakJ, Baer-DubowskaW. The Nrf2-ARE signaling pathway: an update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep, 2016, 69(3): 393-402

[33] ZimtaA, CenariuD, IrimieA, et al.. The Role of Nrf2 Activity in Cancer Development and Progression. Cancers, 2019, 11(11): 1755

[34] Al SaeediFJ. Mangiferin protect oxidative stress against deoxynivalenol induced damages through Nrf2 signalling pathways in endothelial cells. Clin Exp Pharmacol P, 2021, 48(3): 389-400

[35] ZhaoJ, ZhangB, LiS, et al.. Mangiferin increases Nrf2 protein stability by inhibiting its ubiquitination and degradation in human HL60 myeloid leukemia cells. Int J Mol Med, 2014, 33(5): 1348-1354

[36] SuhJH, KanathezhathB, SwapnaS, et al.. Host Nrf2-glutathione redox dysregulation precedes TNF-α elevation and predicts severity of graft versus host disease in experimental transplantation. Blood (ASH Annual Meeting Abstracts), 2012, 120: 4107

[37] RhoadesR, GaballaS. The Role of B Cell Targeting in Chronic Graft-Versus-Host Disease. Biomedicines, 2017, 5(4): 61

[38] PengS, HouY, YaoJ, et al.. Neuroprotection of mangiferin against oxidative damage via arousing Nrf2 signaling pathway in PC12 cells. BioFactors, 2019, 45(3): 381-392

[39] LiS, JinS, ChenW, et al.. Mangiferin alleviates endoplasmic reticulum stress in acute liver injury by regulating the miR-20a/miR-101a-Nrf2 axis. J Nutr Biochem, 2020, 168(4): 365-374