Year: 2017
Type: article
Abstract: Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
Source: Cell Reports
Institutions: Yale University, Umeå University, Howard Hughes Medical Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Howard Hughes Medical Institute, American Heart Association, Glenn Foundation for Medical Research, Yale University, American Foundation for Aging Research, National Institutes of Health, Diabetes Research Center, National Institute on Aging, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Yale Center for Clinical Investigation, Yale School of Medicine
Awards: G1966412456, G2477519282, G256068477, Midcareer Award in Translational Immunology of Aging, Impact of Ketone Metabolites on Inflammasome Deactivation in Gout, G4137943614, Human Brain Ketone Metabolism in Type 1 Diabetes and Hypoglycemia., G5261032657, Reversing brain metabolic adaptations to recurrent hypoglycemia in older adults with type 1 diabetes using a Predictive Low Glucose Management (PLGM) system, G6094022976, G6607210668, Predoctoral Training Program in Virology, Regulation of Brain Glucose Metabolism in Type 1 Diabetes, Thymic adipogenesis and age-related thymic demise, Adaptations of Brain Energy Metabolism to Hypoglycemia, Inflammasomes and the mechanism of thymic demise in aging, Yale University Clinical and Translational Science Award Program, Yale University Clinical and Translational Science Award Program, G8104334537, Thymic adipogenesis and age-related thymic demise, G9000075367, G9000141424, G9000305199, Interdisciplinary Immunology Training Program, Competing Renewal P01, Immune signatures of vaccine responses in vulnerable populations, Yale Diabetes Research Center, Claude D. Pepper Older Americans Independence Center at Yale
OpenAlex ID: W2594548735