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Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects
Javier Traba, … , Richard M. Siegel, Michael N. Sack
Javier Traba, … , Richard M. Siegel, Michael N. Sack
Published November 3, 2015
Citation Information: J Clin Invest. 2015;125(12):4592-4600. https://doi.org/10.1172/JCI83260.
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Clinical Research and Public Health Metabolism Article has an altmetric score of 83

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

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Abstract

BACKGROUND. 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.

METHODS. 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.

RESULTS. 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.

CONCLUSIONS. 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.

TRIAL REGISTRATION. ClinicalTrials.gov NCT02122575 and NCT00442195.

FUNDING. Division of Intramural Research, NHLBI of the NIH.

Authors

Javier Traba, Miriam Kwarteng-Siaw, Tracy C. Okoli, Jessica Li, Rebecca D. Huffstutler, Amanda Bray, Myron A. Waclawiw, Kim Han, Martin Pelletier, Anthony A. Sauve, Richard M. Siegel, Michael N. Sack

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Figure 3

Nutrient status modulates the NLRP3 inflammasome.

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Nutrient status modulates the NLRP3 inflammasome.
(A) ELISA assay measur...
(A) ELISA assay measurement of IL-1β secretion from primary monocytes exposed to 3 mM ATP (n = 8). (B) IL-18 release in the same monocyte studies, showing that both NLRP3 cytokine levels are more robustly secreted in the refed state versus fasted state. (C) TNF-α release in the same monocytes. (D) IL-1β and (E) IL-18 secretion from monocytes primed with 1 ng/ml LPS followed by 5 μM nigericin administration as a second inflammasome trigger (n = 8). The fasting to 3-hour–refed cytokine levels were analyzed using paired 2-tailed t tests. (F) Representative immunoblot analysis showing secretion of mature caspase-1 and mature IL-1β in the supernatants of monocytes treated with LPS and with and without nigericin.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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