老化和炎症 一天可以喝一杯咖啡，保持inflammasome away

StephenW

Editors' Choice AGING AND INFLAMMATION
Could a coffee a day keep the inflammasome away?

    Mallar Bhattacharya

- Author Affiliations

    Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Email: [email protected]

Science Translational Medicine  08 Feb 2017:
Vol. 9, Issue 376,
DOI: 10.1126/scitranslmed.aam6057


Abstract

Increased expression of inflammasome-related genes predicts geriatric morbidity and mortality.

Inflammasomes, protein complexes that regulate expression of interleukin-1 (IL-1) family cytokines, are central to the regulation of a broad variety of inflammatory disease processes, from autoimmunity to cancer to infection. Animal models have suggested increased inflammasome activation with age, but data in humans are limited. A recent report by Furman et al. gives credence to inflammasome activation as a driving factor in age-related hypertension.

Whole blood gene expression was measured by microarray annually in 114 individuals of widely ranging age and genes; they were grouped according to modules based on coordinated expression profiles. Interestingly, two of the modules correlated with age and were functionally related to cytokine production, containing NLRC4 and IL1B among other genes related to inflammasome activity. Focusing on patients in the highest or lowest quartiles, the authors found that high expressors were more likely to be hypertensive, had higher arterial stiffness, and had higher levels of serum cytokines, most prominently IL-1β. Furthermore, high expressors were more likely to have died during 8 years of follow-up.

Mass spectrometry revealed that high expressors had elevated levels of the metabolites adenine and N4A (N4-acetylcytidine), which increased IL-1β and NLRC4 mRNA in primary monocytes, respectively, and together increased IL-1β expression in a caspase-1 and NLRC4-dependent fashion in a monocyte cell line. When injected in mice over several weeks, these metabolites increased blood pressure, particularly when administered along with the prehypertensive stimulus angiotensin II.

This study traces novel connections between metabolism and cardiovascular disease in aging via the inflammasome. The proximate causes of metabolic impairments observed in inflammatory high expressors await further study. Interestingly, caffeine was found to be negatively associated with both inflammatory gene modules, and low expressors of the modules had higher serum levels of caffeine and its metabolites. In vitro, caffeine abolished the positive effect of adenine and N4A on IL-1β expression. Epidemiologic studies have been mixed with regard to the effects of coffee and caffeine on cardiovascular outcomes. However, the specific effects on the inflammasome suggested by this study motivate attention in future trials to the inflammasome as a correlative measure to cardiovascular outcomes.
Highlighted Article

        D. Furman, J. Chang, L. Lartigue, C. R. Bolen, F. Haddad, B. Gaudilliere, E. A. Ganio, G. K. Fragiadakis, M. H. Spitzer, I. Douchet, S. Daburon, J. F. Moreau, G. P. Nolan, P. Blanco, J. Déchanet-Merville, C. L. Dekker, V. Jojic, C. J. Kuo, M. M. Davis, B. Faustin, Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 10.1038/nm.4267 (2017).
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    Copyright © 2017, American Association for the Advancement of Science

StephenW

编辑选择老化和炎症
一天可以喝一杯咖啡，保持炎热的气味吗？

    Mallar Bhattacharya

- 作者关系

    加利福尼亚大学，旧金山，旧金山，加利福尼亚州94143，美国医学系的肺，重症监护，过敏和睡眠分部。电子邮件：[email protected]

科学翻译医学2017年2月08日：
Vol。 9，Issue 376，
DOI：10.1126 / scitranslmed.aam6057


抽象

增加的炎症小体相关基因的表达预示老年发病率和死亡率。

调节白细胞介素-1（IL-1）家族细胞因子表达的蛋白复合物是调节从自身免疫到癌症到感染的多种炎性疾病过程的中枢。动物模型已建议随着年龄增加炎症小体激活，但人类中的数据有限。 Furman等人最近的一份报告给予信息炎症小体激活作为年龄相关的高血压的驱动因素。

通过微阵列每年在114个具有广泛年龄和基因的个体中测量全血基因表达;它们根据基于协调表达谱的模块进行分组。有趣的是，两个模块与年龄相关，并且与细胞因子产生功能相关，其包含与炎症小体活性相关的其它基因中的NLRC4和IL1B。聚焦于最高或最低四分位数的患者，作者发现高表达者更可能是高血压，具有更高的动脉硬度，并具有更高水平的血清细胞因子，最显着的IL-1β。此外，高表达者更可能在8年的随访期间死亡。

质谱显示高表达者具有升高的代谢物腺嘌呤和N4A（N4-乙酰胞苷）的水平，其分别增加原代单核细胞中的IL-1β和NLRC4 mRNA，并且一起增加半胱天冬酶-1和NLRC4-细胞中的IL-1β表达，在单核细胞系中。当在几个星期内在小鼠中注射时，这些代谢物增加血压，特别是当与高血压前刺激血管紧张素II一起施用时。

这项研究追踪代谢和老年心血管疾病通过炎症小体之间的新型联系。在炎性高表达中观察到的代谢障碍的近因原因等待进一步研究。有趣的是，发现咖啡因与两个炎症基因模块负相关，模块的低表达者具有较高的咖啡因及其代谢物的血清水平。在体外，咖啡因废除腺嘌呤和N4A对IL-1β表达的积极作用。流行病学研究在咖啡和咖啡因对心血管结果的影响方面混合。然而，这项研究建议对炎症小体的具体影响，激发了在未来的试验中对炎症小体的注意作为心血管结果的相关测量。
重点文章

        D.Fullman，J.Chang，L.Lartigue，CRBolen，F.Haddad，B.Gaudilliere，EAGanio，GK Fragiadakis，MHSpitzer，I.Douchet，S.Daburon，JFMoultao，GPNolan， J.Déchanet-Merville，CLDekerker，V.Jojic，CJKuo，MMDavis，B.Faustin，Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states。 Nat。 Med。 10.1038 / nm.4267（2017）。
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