Goldberg Emily L, Asher Jennifer L, Molony Ryan D, Shaw Albert C, Zeiss Caroline J, Wang Chao, Morozova-Roche Ludmilla A, Herzog Raimund I, Iwasaki Akiko, Dixit Vishwa Deep
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
Cell Rep. 2017 Feb 28;18(9):2077-2087. doi: 10.1016/j.celrep.2017.02.004.
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
衰老和脂毒性是痛风的两个主要风险因素，它们通过NLRP3炎性小体的激活相互关联。中性粒细胞介导的白细胞介素-1β（IL-1β）产生驱动痛风发作，导致关节破坏、剧痛和发热。然而，影响中性粒细胞炎性小体的代谢产物仍不清楚。在此，我们发现生酮饮食（KD）可增加β-羟基丁酸（BHB）并减轻尿酸盐晶体诱导的痛风，同时不损害对细菌感染的免疫防御。BHB抑制了S100A9原纤维启动和尿酸盐晶体激活的巨噬细胞中的NLRP3炎性小体，这些巨噬细胞在关节中招募炎性中性粒细胞。与喂食生酮饮食的大鼠痛风发作减少一致，BHB以NLRP3依赖的方式阻断了小鼠和人类中性粒细胞中的IL-1β，与年龄无关。从机制上讲，BHB通过减少启动和组装步骤来抑制中性粒细胞中的NLRP3炎性小体。总体而言，我们的研究表明，BHB作为一种已知的替代代谢燃料，也是一种抗炎分子，可能用于治疗痛风。
