# Impact of Ketone Metabolites on Inflammasome Deactivation in Gout

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $357,445

## Abstract

PROJECT SUMMARY:
Gout is a debilitating inflammatory disease caused by urate crystal mediated activation
of the NLRP3 inflammasome. Aging and metabolic syndrome induced by high-fat diets
are major risk factors for Gout. The activation of Nalp3/NLRP3 (for NOD, LRR and pyrin
domain containing) by urate crystals induces recruitment and autocatalytic processing of
cysteine protease caspase-1 in a large cytosolic protein complex called `inflammasome'.
The activation of caspase-1, is required for the cleavage of stored pro-forms of IL-1β and
IL-18 proteins into bioactive secreted cytokines. The assembly of inflammasomes
requires interaction of pyrin domain (PYD) of ASC (for apoptosis-associated speck like
protein containing carboxy terminal CARD) with PYD of Nlrp3 forming a functional
inflammasome complex through CARD-CARD (caspase activation recruitment domain )
interaction of ASC with procaspase-1 zymogen. Therefore, the endogenous pathways
and metabolites that deactivate the inflammasome have high clinical impact. This
proposal is based on our recent findings that ketone metabolite β-hydroxybutyrate (BHB)
blocks the NLRP3 inflammasome to regulate the innate immune response. The ketone
bodies, BHB and acetoacetate (AcAc) are alternate metabolic fuels that support
mammalian survival during periods of starvation by serving as a source of ATP in TCA
cycle when glucose reserves are low. Based on our original findings and strong scientific
premise1, the central hypothesis of this project is that ketogenic substrate switch
underlies the regulatory myeloid responses that dampen metabolic inflammation via
inflammasome deactivation. The corollary is that elevating BHB may serve as a
treatment for Gout. Using both dietary and transgenic approaches that regulate ketone
body metabolism, this proposal will test the mechanism of how BHB controls the
inflammasome activation in macrophages and neutrophils. The long-term goal of this
project is to develop ketone metabolites as therapeutics against Gout.

## Key facts

- **NIH application ID:** 10091969
- **Project number:** 5R01AR070811-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** VISHWA DEEP DIXIT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,445
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091969

## Citation

> US National Institutes of Health, RePORTER application 10091969, Impact of Ketone Metabolites on Inflammasome Deactivation in Gout (5R01AR070811-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10091969. Licensed CC0.

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