Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Department of Anesthesiology and Perioperative Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
Mediators Inflamm. 2020 May 18;2020:6959741. doi: 10.1155/2020/6959741. eCollection 2020.
Following traumatic insult and associated pathogen infection, innate immunity is activated during the perioperative period, especially the NLRP3 inflammasome in macrophages. The neuroendocrine response is also rapidly activated to regulate excessive inflammation; however, the molecular mechanisms are still not completely clear. This study is aimed at investigating the modulation of NLRP3 inflammasome priming by endogenous glucocorticoids (corticosterone, CORT) and its relationship with xanthine oxidase (XO). RAW264.7 murine macrophages were stimulated with LPS (1 g/ml). LPS-induced NLRP3 expression was pretreated by CORT at different concentrations (0-900 ng/ml). Then, the effect of higher concentrations of CORT (700 ng/ml) on LPS-induced NLRP3 expression and the effect of allopurinol (250 g/ml) were observed. Finally, the effects of a CORT antagonist (RU486) on XO expression and activity and NLRP3 expression in macrophages were further analyzed. Supernatant levels IL-1 and IL-18 were measured. The results showed that LPS-induced NLRP3 expression was upregulated further by pretreatment with CORT (300 ng/ml) ( < 0.05); however, higher concentrations of CORT (greater than 700 ng/ml) downregulated NLRP3 expression ( < 0.01) and the expression and activity of XO ( < 0.05 and < 0.01, respectively). Allopurinol significantly inhibited NLRP3 expression. However, XO expression and activity, NLRP3 expression, and supernatant IL-1 and IL-18 levels were significantly increased in the RU486 group compared with the CORT group. In conclusion, our results suggested that CORT inhibits LPS-induced NLRP3 inflammasome priming in macrophages. The underlying mechanism is related to the modulation of XO expression and activity, which may be involved in priming and activating the NLRP3 inflammasome.
在创伤性损伤和相关病原体感染后，固有免疫在围手术期被激活，特别是巨噬细胞中的 NLRP3 炎性体。神经内分泌反应也迅速被激活以调节过度炎症；然而，其分子机制尚不完全清楚。本研究旨在探讨内源性糖皮质激素（皮质酮，CORT）对 NLRP3 炎性体引发的调节及其与黄嘌呤氧化酶（XO）的关系。用 LPS（1μg/ml）刺激 RAW264.7 鼠巨噬细胞。用不同浓度（0-900ng/ml）的 CORT 预处理 LPS 诱导的 NLRP3 表达。然后观察更高浓度的 CORT（700ng/ml）对 LPS 诱导的 NLRP3 表达的影响和别嘌呤醇（250μg/ml）的作用。最后，进一步分析 CORT 拮抗剂（RU486）对巨噬细胞中 XO 表达和活性以及 NLRP3 表达的影响。测量上清液中 IL-1 和 IL-18 的水平。结果表明，CORT（300ng/ml）预处理进一步上调 LPS 诱导的 NLRP3 表达（ < 0.05）；然而，更高浓度的 CORT（大于 700ng/ml）下调 NLRP3 表达（ < 0.01）和 XO 的表达和活性（ < 0.05 和 < 0.01，分别）。别嘌呤醇显著抑制 NLRP3 表达。然而，与 CORT 组相比，RU486 组的 XO 表达和活性、NLRP3 表达以及上清液中 IL-1 和 IL-18 的水平均显著增加。综上所述，我们的结果表明 CORT 抑制 LPS 诱导的巨噬细胞 NLRP3 炎性体引发。其潜在机制与 XO 表达和活性的调节有关，可能涉及 NLRP3 炎性体的引发和激活。
