Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes
Suppression of Syk activation by resveratrol inhibits MSU crystal-induced inflammation in human monocytes
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DOI：
10.1007/s00109-018-01736-y
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发表时间：
2019-03-01
影响因子：
4.7
通讯作者：
Lee, Won-Woo
中科院分区：
文献类型：
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作者：
Chung, Yeon-Ho;Kim, Hee Young;Lee, Won-Woo
尿酸单钠（MSU）晶体是一种内源性无菌颗粒，已被确定为一种有效的损伤相关分子模式（DAMP）。在人类中，通过MSU诱导的单核细胞/巨噬细胞中的NLRP 3炎性体活化诱导IL-1产生是痛风性关节炎发病机制的原因。最近报道，在这种疾病的小鼠模型中，白藜芦醇减少MSU诱导的痛风性关节炎复发。尽管其抗炎作用已被证实，但对白藜芦醇介导的MSU激活的单核细胞中IL-1产生抑制的机制仍知之甚少。在这里，我们表明，白藜芦醇通过抑制Syk激活抑制MSU晶体刺激的人原代单核细胞分泌活性IL-1。研究从头蛋白合成的代谢标记和下拉测定清楚地表明，白藜芦醇处理后，由于Syk和p38磷酸化的降低，单核细胞内IL-1前体的合成迅速受到抑制。白藜芦醇还通过抑制ASC的寡聚化来抑制MSU刺激的单核细胞中的NLRP 3炎性体活化。此外，白藜芦醇通过减少IL-1的产生和抑制中性粒细胞在MSU介导的腹膜炎小鼠模型中的募集而发挥有益作用。我们的研究结果表明，白藜芦醇通过翻译后调节IL-1的产生发挥抗炎作用，因此，可能被证明是有益的MSU晶体介导的无菌inflammation.Key messageResveratrol通过Syk和p38对pro-IL-1的合成有负面影响。白藜芦醇抑制ASC的寡聚化。白藜芦醇是有益的MSU诱导的腹膜炎小鼠模型。
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-1 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-1 production in MSU-activated monocytes remain poorly understood. Here, we show that resveratrol suppresses secretion of active IL-1 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-1 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-1 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-1 production and, thus, may prove beneficial for the treatment of MSU crystal-mediated sterile inflammation.Key messageResveratrol has negative effects on pro-IL-1 synthesis through Syk and p38.Resveratrol inhibits oligomerization of ASC.Resveratrol is beneficial in a mouse model of MSU-induced peritonitis.