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Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects
Open accessAbstract
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.
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“In addition, they have demonstrated beneficial pharmacological activities in acute renal failure [28], anti-inflammatory [29–31], cardio and vasoprotective actions [32–35], telomere lengthening [36, 37•], extend lifespan and promote health in various organisms, from yeasts to mammals [10, 14, 15, 38].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [30]
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“Additionally, NR decreased Interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) secretion in monocytes and macrophages from healthy volunteers, with the most significant reductions in monocytes of over 50% for IL-1β (from approximately 22,000 to 10,000 pg/mL) and over 75% for TNF-α (from above 2000 to less than 500 pg/mL). In macrophages, the most pronounced reduction was around 20% for”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [30]
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“NR reduced acetylation of SOD2 and isocitrate dehydrogenase 2, while increasing mitochondrial SOD2 activity, thereby reducing mitochondrial ROS levels.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [30]
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“Consistent with NR’s known role in increasing NAD+ levels and consequently SIRT3 activation, the 24-h administration of NR (amount not described) to PBMCs from healthy subjects replicated the fasting effect of blunting NLRP3 inflammasome activation and enhancing mitochondrial quality control through SIRT3 [30].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [30]
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“More importantly, SIRT3 can directly bind and deacetylate SOD2, leading to increased SOD2 activity and subsequently exerting significant effects on mtROS homeostasis and NLRP3 inflammasome activation.18, 19, 20”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [19]
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“Traba et al19 additionally confirmed that a 24‐hour fast in human subjects activates SIRT3 biology, thereby increasing SOD2 activity, in turn conferring resistance to NLRP3 inflammasome activation via blunting of the mtROS level.19”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [19]
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Metadata
- Authors
- Traba, J., Kwarteng-Siaw, M., Okoli, T. C., Li, J., Huffstutler, R. D., Bray, A., Waclawiw, M. A., Han, K., Pelletier, M., Sauve, A. A., Siegel, R. M., & Sack, M. N.
- Affiliations
- National Heart, Lung, and Blood Institute (US)
- National Institutes of Health (US)
- Weill Cornell Medicine (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-11-03
- Volume
- 125
- Issue
- 12
- Pages
- 4592-4600
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4665779
- OpenAlex
- W2131482219
- Cited by
- 180
- References
- 48
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 20 · 2023: 12 · 2022: 26 · 2021: 14 · 2020: 22 · 2019: 16 · 2018: 14 · 2017: 16 · 2016: 10 · 2015: 1
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL005102‐11, Z01HL005102)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Keywords
- NLRP3 inflammasome, fasting, refeeding, SIRT3, sirtuins, nicotinamide riboside, mitochondrial homeostasis, mitochondrial reactive oxygen species, macrophages, inflammation, metabolic dysfunction
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Adult, Carrier Proteins, Eating, Fasting, Female, Humans, Male, Mitochondria, Niacinamide, Pyridinium Compounds, Inflammasomes
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