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-1? 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 ?-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.

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STATEMENT Gout is caused by urate crystal deposition in the joints that cause severe inflammation, pain and joint destruction. There are currently few treatment options for Gouty flares which are episodes of severe pain. The main challenge to manage this disease is the inability to specifically block an immune system pathway called the inflammasome. We have now found that body's endogenous metabolite, typically produced upoin fasting, called ketone body, can be harnessed to inhibit the inflammasome. Therefore, the goal of this project to develop ketone bodies as therapeutic for treatment against Gout.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Mao, Su-Yau
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Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
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Ravussin, Anthony; Youm, Yun-Hee; Sander, Jil et al. (2018) Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity. Cell Rep 24:1085-1092.e6
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Camell, Christina D; Sander, Jil; Spadaro, Olga et al. (2017) Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550:119-123
Goldberg, Emily L; Asher, Jennifer L; Molony, Ryan D et al. (2017) ?-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep 18:2077-2087