Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes
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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.
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.
KeywordsMSU Resveratrol IL-1β NLRP3 inflammasome Syk Gouty arthritis
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
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.
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