Could a coffee a day keep the inflammasome away?

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Science Translational Medicine  08 Feb 2017:
Vol. 9, Issue 376, eaam6057
DOI: 10.1126/scitranslmed.aam6057


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.

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