Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Department of Biochemistry, Shimane University School of Medicine, Izumo, Japan.
Mod Rheumatol. 2021 Jan;31(1):270-275. doi: 10.1080/14397595.2020.1740410. Epub 2020 Mar 30.
Gout is an inflammatory arthropathy caused by the deposition of monosodium urate (MSU). The synthesis and release of IL-1β is crucial for MSU-induced synovial inflammation. The aim of the present study was to investigate the mechanism of MSU crystal-induced autoinflammatory processes.
studies were used to evaluate the role of IL-6 in inflammasome activation in human neutrophils cultured with MSU crystals. Human neutrophils were stimulated with MSU in the presence or absence of IL-6 priming to determine NLRP3 inflammasome activation and subsequent cleaved caspase-1 induction or IL-1β production.
IL-6 or MSU stimulation alone did not result in the efficient IL-1β production from human neutrophils. However, MSU stimulation induced marked IL-1β production from IL-6-primed neutrophils. Pretreatment with baricitinib, which blocks IL-6 receptor signaling, prevented MSU-induced cleaved caspase-1 or IL-1β induction in IL-6-primed neutrophils. Tocilizumab pretreatment also inhibited MSU-mediated IL-1β production from IL-6-primed neutrophils.
Priming of human neutrophils with IL-6 promotes uric acid-mediated IL-1β secretion in the absence of microbial stimulation. These results suggest that an endogenous cytokine, IL-6, is involved in MSU-mediated NLRP3 inflammasome activation and subsequent IL-1β production from innate immune cells and has a crucial role in MSU crystal-induced synovial inflammation. These findings provide insights into uric acid-mediated autoinflammation in the innate immune system.
痛风是一种由单钠尿酸盐（MSU）沉积引起的炎症性关节病。IL-1β 的合成和释放对于 MSU 诱导的滑膜炎症至关重要。本研究旨在探讨 MSU 晶体诱导的自身炎症过程的机制。
研究评估了 IL-6 在人中性粒细胞培养物中 MSU 晶体诱导的炎症小体激活中的作用。在存在或不存在 IL-6 引发的情况下，用 MSU 刺激人中性粒细胞，以确定 NLRP3 炎症小体的激活以及随后的切割半胱天冬酶-1 诱导或 IL-1β 产生。
IL-6 或 MSU 单独刺激不会导致人中性粒细胞有效产生 IL-1β。然而，MSU 刺激诱导了经 IL-6 引发的中性粒细胞中明显的 IL-1β 产生。用阻断 IL-6 受体信号的巴瑞替尼预处理可防止 MSU 诱导的经 IL-6 引发的中性粒细胞中切割半胱天冬酶-1 或 IL-1β 诱导。托珠单抗预处理也抑制了 MSU 介导的经 IL-6 引发的中性粒细胞中 IL-1β 的产生。
IL-6 引发人中性粒细胞可促进尿酸介导的 IL-1β 分泌，而无需微生物刺激。这些结果表明，内源性细胞因子 IL-6 参与了 MSU 介导的 NLRP3 炎症小体激活以及随后的先天免疫细胞中 IL-1β 的产生，并在 MSU 晶体诱导的滑膜炎症中起关键作用。这些发现为尿酸介导的先天免疫系统自身炎症提供了深入了解。
