RT Journal Article
SR Electronic
T1 Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1506
OP 1514
DO 10.1136/annrheumdis-2020-217342
VO 79
IS 11
A1 Felix Renaudin
A1 Lucie Orliaguet
A1 Florence Castelli
A1 François Fenaille
A1 Aurelie Prignon
A1 Fawaz Alzaid
A1 Christele Combes
A1 Aurélie Delvaux
A1 Yasmina Adimy
A1 Martine Cohen-Solal
A1 Pascal Richette
A1 Thomas Bardin
A1 Jean-Pierre Riveline
A1 Nicolas Venteclef
A1 Frédéric Lioté
A1 Laure Campillo-Gimenez
A1 Hang-Korng Ea
YR 2020
UL http://ard.bmj.com/content/79/11/1506.abstract
AB Objective Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response.Methods Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition.Results We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo.Conclusion In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.