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

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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.

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Funding

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.

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Author notes

  1. Yeon-Ho Chung

    Present address: Department of Orthopedics and Rehabilitation, Yale University School of Medicine, 330 Cedar Street, Tompkins Memorial Pavilion, New Haven, CT, 06520-8071, USA

  2. Hee Young Kim and Bo Ruem Yoon contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, and BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

    Yeon-Ho Chung, Yeon Jun Kang & Won-Woo Lee

  2. Department of Microbiology and Immunology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

    Hee Young Kim, Bo Ruem Yoon & Won-Woo Lee

  3. Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, South Korea

    Won-Woo Lee

  4. Seoul National University Hospital Biomedical Research Institute, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

    Won-Woo Lee

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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

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Correspondence to Won-Woo Lee.

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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.

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Chung, YH., Kim, H.Y., Yoon, B.R. et al. Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes. J Mol Med 97, 369–383 (2019). https://doi.org/10.1007/s00109-018-01736-y

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