Advertisement

Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes

  • Yeon-Ho Chung
  • Hee Young Kim
  • Bo Ruem Yoon
  • Yeon Jun Kang
  • Won-Woo LeeEmail author
Original Article
  • 49 Downloads

Abstract

Monosodium urate (MSU) crystals are an endogenous sterile particulate that has been identified as a potent damage-associated molecular pattern (DAMP). In humans, the induction of IL-1β production through MSU-induced NLRP3 inflammasome activation in monocytes/macrophages is responsible for pathogenesis of gouty arthritis. It was recently reported that in a murine model of this disease, resveratrol decreases MSU-induced recurrent attacks of gouty arthritis. Despite its demonstrated anti-inflammatory effects, the mechanisms underlying resveratrol-mediated repression of IL-1β production in MSU-activated monocytes remain poorly understood. Here, we show that resveratrol suppresses secretion of active IL-1β by human primary monocytes stimulated with MSU crystals through suppression of Syk activation. Metabolic labeling and pull-down assays to investigate de novo protein synthesis clearly demonstrated that intracellular pro-IL-1β synthesis is rapidly repressed in monocytes after resveratrol treatment due to decreased phosphorylation of Syk and p38. Resveratrol also inhibited NLRP3 inflammasome activation in MSU-stimulated monocytes by suppressing oligomerization of ASC. Furthermore, resveratrol exerted a beneficial effect by reducing IL-1β production and inhibiting neutrophil recruitment in a mouse model of MSU-mediated peritonitis. Our findings suggest that resveratrol exerts anti-inflammatory effects via post-translational regulation of IL-1β production and, thus, may prove beneficial for the treatment of MSU crystal-mediated sterile inflammation.

Key message

  • Resveratrol has negative effects on pro-IL-1β synthesis through Syk and p38.

  • Resveratrol inhibits oligomerization of ASC.

  • Resveratrol is beneficial in a mouse model of MSU-induced peritonitis.

Keywords

MSU Resveratrol IL-1β NLRP3 inflammasome Syk Gouty arthritis 

Notes

Author contributions

Y-H.C.: designed the study, performed most of the experiments, data collection and analysis, and drafted manuscript. H.Y.K., B.R.Y., and Y.J.K.: performed the experiments, and data collection and analysis. W-W.L.: conceived the study, participated in its design and coordination, performed data analysis, and writing of manuscript

Funding information

This study was supported partially by grants (HI13C0954 and HI13C0715 to W.-W.L.) from the Korean Health Technology R&D Project, Ministry of Health and Welfare, and grants (NRF-2018R1A2B2006310 to W.-W.L. and NRF-2015R1C1A1A01054454 to Y.H.C.) from the National Research Foundation, Republic of Korea.

Compliance with ethical standards

The study protocols were reviewed and approved by the IRB of Seoul National University Hospital. Peripheral blood of healthy volunteers was drawn after obtaining the written informed consent.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

109_2018_1736_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1.22 mb)

References

  1. 1.
    Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837CrossRefGoogle Scholar
  2. 2.
    Liston A, Masters SL (2017) Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol 17:208–214CrossRefGoogle Scholar
  3. 3.
    Franklin BS, Mangan MS, Latz E (2016) Crystal formation in inflammation. Annu Rev Immunol 34:173–202CrossRefGoogle Scholar
  4. 4.
    Rock KL, Kataoka H, Lai JJ (2013) Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 9:13–23CrossRefGoogle Scholar
  5. 5.
    McCarty DJ, Hollander JL (1961) Identification of urate crystals in gouty synovial fluid. Ann Intern Med 54:452–460CrossRefGoogle Scholar
  6. 6.
    Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, Akira S, Rock KL (2006) MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 116:2262–2271CrossRefGoogle Scholar
  7. 7.
    Jesus AA, Goldbach-Mansky R (2014) IL-1 blockade in autoinflammatory syndromes. Annu Rev Med 65:223–244CrossRefGoogle Scholar
  8. 8.
    Bryant C, Fitzgerald KA (2009) Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 19:455–464CrossRefGoogle Scholar
  9. 9.
    Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687CrossRefGoogle Scholar
  10. 10.
    Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schroder GF, Fitzgerald KA, Wu H, Egelman EH (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193–1206CrossRefGoogle Scholar
  11. 11.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241CrossRefGoogle Scholar
  12. 12.
    Shakibaei M, Harikumar KB, Aggarwal BB (2009) Resveratrol addiction: to die or not to die. Mol Nutr Food Res 53:115–128CrossRefGoogle Scholar
  13. 13.
    Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science (New York, NY) 275:218–220CrossRefGoogle Scholar
  14. 14.
    de la Lastra CA, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:1156–1160CrossRefGoogle Scholar
  15. 15.
    Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, Longo DL, Belman JP, Malagon MM, Navas P, Sanghvi M, Moaddel R, Tilmont EM, Herbert RL, Morrell CH, Egan JM, Baur JA, Ferrucci L, Bogan JS, Bernier M, de Cabo R (2013) Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab 18:533–545CrossRefGoogle Scholar
  16. 16.
    Libby P, Ridker PM, Hansson GK (2009) Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 54:2129–2138CrossRefGoogle Scholar
  17. 17.
    Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117CrossRefGoogle Scholar
  18. 18.
    Huang Z, Wang C, Wei L, Wang J, Fan Y, Wang L, Wang Y, Chen T (2008) Resveratrol inhibits EMMPRIN expression via P38 and ERK1/2 pathways in PMA-induced THP-1 cells. Biochem Biophys Res Commun 374:517–521CrossRefGoogle Scholar
  19. 19.
    Zong Y, Sun L, Liu B, Deng YS, Zhan D, Chen YL, He Y, Liu J, Zhang ZJ, Sun J, Lu D (2012) Resveratrol inhibits LPS-induced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PLoS One 7:e44107CrossRefGoogle Scholar
  20. 20.
    Kowalski J, Samojedny A, Paul M, Pietsz G, Wilczok T (2005) Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol Rep 57:390–394Google Scholar
  21. 21.
    Chen H, Zheng S, Wang Y, Zhu H, Liu Q, Xue Y, Qiu J, Zou H, Zhu X (2016) The effect of resveratrol on the recurrent attacks of gouty arthritis. Clin Rheumatol 35:1189–1195CrossRefGoogle Scholar
  22. 22.
    Chung YH, Kim DH, Lee WW (2016) Monosodium urate crystal-induced pro-interleukin-1beta production is post-transcriptionally regulated via the p38 signaling pathway in human monocytes. Sci Rep 6:34533CrossRefGoogle Scholar
  23. 23.
    Jin HM, Kim TJ, Choi JH, Kim MJ, Cho YN, Nam KI, Kee SJ, Moon JB, Choi SY, Park DJ, Lee SS, Park YW (2014) MicroRNA-155 as a proinflammatory regulator via SHIP-1 down-regulation in acute gouty arthritis. Arthritis Res Ther 16:R88CrossRefGoogle Scholar
  24. 24.
    Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6:168–173CrossRefGoogle Scholar
  25. 25.
    de la Lastra CA, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 49:405–430CrossRefGoogle Scholar
  26. 26.
    Villa-Cuesta E, Boylan JM, Tatar M, Gruppuso PA (2011) Resveratrol inhibits protein translation in hepatic cells. PLoS One 6:e29513CrossRefGoogle Scholar
  27. 27.
    Lee MJ, Feliers D, Sataranatarajan K, Mariappan MM, Li M, Barnes JL, Choudhury GG, Kasinath BS (2010) Resveratrol ameliorates high glucose-induced protein synthesis in glomerular epithelial cells. Cell Signal 22:65–70CrossRefGoogle Scholar
  28. 28.
    Mondal K, Sirenko OI, Lofquist AK, Morris JS, Haskill JS, Watson JM (2000) Differential role of tyrosine phosphorylation in adhesion-induced transcription, mRNA stability, and cytoskeletal organization in human monocytes. J Leukoc Biol 67:216–225CrossRefGoogle Scholar
  29. 29.
    Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R (2006) Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol (Baltimore, Md : 1950) 177:6370–6378CrossRefGoogle Scholar
  30. 30.
    Ng G, Sharma K, Ward SM, Desrosiers MD, Stephens LA, Schoel WM, Li T, Lowell CA, Ling CC, Amrein MW, Shi Y (2008) Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29:807–818CrossRefGoogle Scholar
  31. 31.
    Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD (2008) Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation. Mol Cell Biol 28:3538–3547CrossRefGoogle Scholar
  32. 32.
    Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M (2013) Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 14:1247–1255CrossRefGoogle Scholar
  33. 33.
    Poulsen MM, Fjeldborg K, Ornstrup MJ, Kjaer TN, Nohr MK, Pedersen SB (2015) Resveratrol and inflammation: challenges in translating pre-clinical findings to improved patient outcomes. Biochim Biophys Acta 1852:1124–1136CrossRefGoogle Scholar
  34. 34.
    Imler TJ Jr, Petro TM (2009) Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+IL-10+ T cells, CD4(−) IFN-gamma+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 9:134–143CrossRefGoogle Scholar
  35. 35.
    Xuzhu G, Komai-Koma M, Leung BP, Howe HS, McSharry C, McInnes IB, Xu D (2012) Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 71:129–135CrossRefGoogle Scholar
  36. 36.
    Lin JN, Lin VC, Rau KM, Shieh PC, Kuo DH, Shieh JC, Chen WJ, Tsai SC, Way TD (2010) Resveratrol modulates tumor cell proliferation and protein translation via SIRT1-dependent AMPK activation. J Agric Food Chem 58:1584–1592CrossRefGoogle Scholar
  37. 37.
    Valimaki E, Miettinen JJ, Lietzen N, Matikainen S, Nyman TA (2013) Monosodium urate activates Src/Pyk2/PI3 kinase and cathepsin dependent unconventional protein secretion from human primary macrophages. Molecular & cellular proteomics : MCP 12:749–763CrossRefGoogle Scholar
  38. 38.
    Kulkarni SS, Canto C (2015) The molecular targets of resveratrol. Biochim Biophys Acta 1852:1114–1123CrossRefGoogle Scholar
  39. 39.
    Robbins GR, Wen H, Ting JP (2014) Inflammasomes and metabolic disorders: old genes in modern diseases. Mol Cell 54:297–308CrossRefGoogle Scholar
  40. 40.
    Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R (2005) Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52:2936–2946CrossRefGoogle Scholar
  41. 41.
    Mocsai A, Ruland J, Tybulewicz VL (2010) The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 10:387–402CrossRefGoogle Scholar
  42. 42.
    Lin YC, Huang DY, Wang JS, Lin YL, Hsieh SL, Huang KC, Lin WW (2015) Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization. J Leukoc Biol 97:825–835CrossRefGoogle Scholar
  43. 43.
    Piotrowska H, Kucinska M, Murias M (2012) Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res 750:60–82CrossRefGoogle Scholar
  44. 44.
    Jiang M, Liu R, Chen Y, Zheng Q, Fan S, Liu P (2014) A combined experimental and computational study of Vam3, a derivative of resveratrol, and Syk interaction. Int J Mol Sci 15:17188–17203CrossRefGoogle Scholar
  45. 45.
    Neves AR, Nunes C, Amenitsch H, Reis S (2016) Resveratrol interaction with lipid bilayers: a synchrotron X-ray scattering study. Langmuir 32:12914–12922CrossRefGoogle Scholar
  46. 46.
    Delmas D, Aires V, Colin DJ, Limagne E, Scagliarini A, Cotte AK, Ghiringhelli F (2013) Importance of lipid microdomains, rafts, in absorption, delivery, and biological effects of resveratrol. Ann N Y Acad Sci 1290:90–97CrossRefGoogle Scholar
  47. 47.
    Colin D, Limagne E, Jeanningros S, Jacquel A, Lizard G, Athias A, Gambert P, Hichami A, Latruffe N, Solary E, Delmas D (2011) Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prev Res (Phila) 4:1095–1106CrossRefGoogle Scholar
  48. 48.
    Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, Seamone ME, Vilaysane A, Mucsi AD, Fong Y, Prenner E, Ling CC, Tschopp J, Muruve DA, Amrein MW, Shi Y (2011) Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med 17:479–487CrossRefGoogle Scholar
  49. 49.
    Corr EM, Cunningham CC, Dunne A (2016) Cholesterol crystals activate Syk and PI3 kinase in human macrophages and dendritic cells. Atherosclerosis 251:197–205CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical Sciences, and BK21 Plus Biomedical Science ProjectSeoul National University College of MedicineSeoulSouth Korea
  2. 2.Department of Orthopedics and RehabilitationYale University School of MedicineNew HavenUSA
  3. 3.Department of Microbiology and ImmunologySeoul National University College of MedicineSeoulSouth Korea
  4. 4.Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious DiseasesSeoul National University College of MedicineSeoulSouth Korea
  5. 5.Seoul National University Hospital Biomedical Research InstituteSeoulSouth Korea

Personalised recommendations