Spermidine Reproduces the Anti-Inflammatory Effects of Intermittent Fasting and Prevents Urate and Calcium Pyrophosphate Crystal-Induced Inflammation.

Abstract

Gout caused by the formation of monosodium urate (MSU) crystals and calcium pyrophosphate (CPP) deposition disease are two major types of microcrystalline pathologies in adults. They are responsible for recurrent flares that rely on interleukin (IL) 1β via activation of the NLRP3 inflammasome. Intermittent fasting (IF) is a nonpharmacologic intervention that improves age-related diseases and reduces inflammation. In an air pouch model, crystal-induced inflammation was compared between mice fed ad libitum and mice under IF. Systemic (liver and serum) and local (air pouch cavity) modifications were evaluated by metabolomics analysis. The anti-inflammatory potential of metabolites was tested in vitro and in vivo. We observe that two nonconsecutive days of fasting during one week significantly prevents the inflammation provoked by MSU and CPP crystal injection into the air pouch cavity in a mouse model. This short-term fasting is associated with increased serum abundances of numerous anti-inflammatory metabolites, including β-hydroxybutyrate and spermidine (SPD), a polyamine able to reproduce biologic effects of IF. Conversely, crystal stimulation in mice fed ad libitum decreases the local production of these metabolites in the air pouch membrane. Supplementation of SPD reproduces the anti-inflammatory effect of IF and prevents crystal-induced inflammation through inhibition of NF-κB and NLRP3 inflammasome. Finally, down-regulation of SPD/spermine acetyltransferase 1, which encodes the enzyme that degrades SPD, reduces IL-1β production induced by crystal stimulation. In summary, we have identified several metabolites that recapitulate the anti-inflammatory effects of IF and could be used as IF mimetics to prevent microcrystal inflammation.