Traba Javier, Kwarteng-Siaw Miriam, Okoli Tracy C, Li Jessica, Huffstutler Rebecca D, Bray Amanda, Waclawiw Myron A, Han Kim, Pelletier Martin, Sauve Anthony A, Siegel Richard M, Sack Michael N
J Clin Invest. 2015 Nov 3;125(12):4592-600. doi: 10.1172/JCI83260.
Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.
We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.
In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.
Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.
ClinicalTrials.gov NCT02122575 and NCT00442195.
Division of Intramural Research, NHLBI of the NIH.
NLRP3炎性小体的激活与代谢功能障碍相关，间歇性禁食已被证明可改善NLRP3炎性小体相关疾病的临床表现。由于作为损伤相关分子模式发挥作用的线粒体扰动会加剧NLRP3炎性小体的激活，我们研究了禁食是否通过沉默调节蛋白介导的线粒体完整性增强来抑制炎性小体的激活。
我们对19名健康志愿者进行了一项临床研究。每位受试者进行24小时禁食，然后进食固定热量的餐食。在禁食和进食状态下采集血液，分析NRLP3炎性小体的激活情况。我们又招募了另外一组8名健康志愿者，以评估沉默调节蛋白激活剂烟酰胺核糖对NLRP3炎性小体激活的影响。
在禁食/再进食研究中，与再进食状态相比，个体在禁食状态下NLRP3炎性小体的激活较少。在人巨噬细胞系中，富含线粒体的沉默调节蛋白去乙酰化酶SIRT3的缺失与过量的线粒体ROS产生相关，增加了NLRP3炎性小体的激活。此外，在培养细胞以及从健康志愿者和再进食个体中提取的白细胞中，基因和药理学方法激活SIRT3可抑制NLRP3活性，同时增强线粒体功能，但在禁食期间采集的白细胞中则无此作用。
总之，我们的数据表明营养水平部分通过SIRT3介导的线粒体稳态控制来调节NLRP3炎性小体。此外，这些结果表明，依赖去乙酰化酶的炎性小体减弱可能适用于人类疾病的靶向治疗。
ClinicalTrials.gov NCT02122575和NCT00442195。
美国国立卫生研究院国立心肺血液研究所内部研究部。
