β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares

Abstract

Summary Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of NLRP3 inflammasome. Neutrophil-mediated production of 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 beta-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 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.

BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer's disease

“…D-F, Lentiviral interference vector of GPR109A inhibited the BHBA-mediated change in APP and NEP mRNA expression (n = 3, means ± SD, Student's t test, **P < .01, ***P < .001). The primary circulating ketone is 3-hydroxybutyrate or BHBA, which has been demonstrated to show an anti-inflammatory effect in various diseases 28,29 contributing to its neuroprotective effects. H,I, Quantitative analysis of the expression of APP and NEP in HT22 cells in different groups (n = 3, means ± SD, Student's t test, *P < .05, **P < .01, ***P < .001) other than the treatment of epileptic patients.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…A recent study using longitudinal cohort data found higher levels of IL1Beta and IL‐6 were correlated to age‐related illnesses and shorter lifespan (Furman et al ., 2017). Another study showed inhibition of serum IL‐1β alleviated gout‐related symptoms (aging‐related inflammatory disease) in monosodium urate (MSU) crystals‐induced murine model (Goldberg et al ., 2017). Therefore, inhibition of SASP will be critical for limiting inflammaging.…”

Metabolic regulation of inflammasomes in inflammation

“…Accordingly, BHB has been shown to suppress K + efflux, thus dampening NLRP3 inflammasome activation in macrophages . A later study also has revealed BHB blocks the priming and assembly steps of the NLRP3 inflammasome in neutrophils …”