Impact of Ketone Metabolites on Inflammasome Deactivation in Gout

酮代谢物对痛风炎症小体失活的影响

• 批准号: 9216426
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216426
• 关键词: Ablation; Acetoacetates; Acute; Adipose tissue; Aging; Apoptosis; CASP1 gene; Carbon; Caspase; Cells; Citric Acid Cycle; Clinical; Coenzyme A; Complex; Crystal Formation; Crystallization; Data; Detection; Development; Diet; Disease; Enzyme Precursors; Enzymes; Fasting; Fever; Flare; Generations; Glucose; Glycolysis Inhibition; Goals; Gout; Gouty Arthritis; High Fat Diet; Human; Immune; Immune system; In Vitro; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1 beta; Interleukin-18; Joints; Ketone Bodies; Ketones; Label; Lipids; Liver; LoxP-flanked allele; Lyase; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolic syndrome; Metabolism; Methods; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Nonesterified Fatty Acids; Pain; Pathology; Pathway interactions; Patients; Production; Proteins; Protons; Rattus; Recruitment Activity; Regulation; Resolution; Risk Factors; Role; S100A8 gene; Signal Transduction; Source; Starvation; Testing; Therapeutic; Tissues; Transgenic Organisms; Urate; Work; base; beta-Hydroxybutyrate; cell type; cytokine; granulocyte; immunoregulation; in vivo; joint destruction; ketogenesis; ketogenic diet; ketogentic; macrophage; marenostrin; monocyte; neutrophil; novel; protein complex; response

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.

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