Background/Purpose: Inflammation induced by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals depends on interleukin (IL)-1β activated by the NLRP3 inflammasome. The inflammatory response can be modulated by diet, fasting, and caloric restriction.

Ojective: To determine whether intermittent fasting reduces MSU and CPP crystal-induced inflammation.

Methods: Crystal-induced inflammation was assessed using both types of crystals in vivo in the air pouch model in 8-week-old wild-type male mice fed either with a normal ad libitum diet or intermittent fasting (IF) (every over day fast, 2 days during 1 week). Inflammatory cytokine production (IL1β and CXCL-1) was assessed in the pouch lavages and the cellular infiltrate analyzed by histology (H&E staining). Metabolomic analyses were performed by high-performance liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) on air pouch membrane, serum, and liver samples.

In vitro, human monocytes THP-1 were stimulated by sterile synthetic crystals of MSU and CPP while the production of inflammatory cytokines was quantified by ELISA.

To assess the role of glutamine/glutamate metabolism pathway related to IF in microcrystalline disease, the concentrations of glutamine/glutamate in synovial fluids (SF) from patients with gout, CPP-related disease and osteoarthritis (OA) were quantified by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS).

Results: Inflammation induced by MSU and CPP crystals was drastically decreased by IF compared with normal diet: IL-1β (MSU 0.0 vs. 30.0 pg/ml; CPP 0.0 vs. 47.5 pg/ml p< 0.0001); CXCL-1 (MSU 67.5 vs. 186.8 pg/ml, CPP 156.1 vs. 549.5 pg/ml, p< 0.005); as were cell infiltration assessed by number of cells in the air pouch lavages (MSU 0.2 x 106 vs. 1.1 x 106 ; CPP 0.4 x 106 vs 2.9 x 106; p< 0.0001) and membrane histology semi-quantitative score (MSU 0.6 vs 3.0; CPP 0.8 vs 2.7; p< 0.0001).

Reduction of inflammation by IF was associated with significant changes in membrane, serum and liver metabolites. Many metabolic pathways were altered by IF such as galactose, starch, sucrose, aspartate, glutamate, alanine and arginine metabolism. Interestingly, the glutamine and glutamate metabolic pathway was enriched in serum, membrane and liver compartments.

Glutamine/glutamate involvement in microcrystal-induced inflammation was evidenced in SFs. The glutamine/glutamate ratio was decreased in synovial fluids of crystal-related diseases compared to OA (gout 1.4 and CPP 6.1 vs OA 9.4, p< 0.0001 and p< 0.05 respectively).

In vitro, crystal-induced inflammatory cytokine production was decreased by overnight serum deprivation (IL-1β: MSU 1446 vs 5464 pg/ml; CPP 3670 vs 7797 pg/ml, p< 0.005; TNF-α: MSU 7.0 vs 47.0 pg/ml; CPP 15.6 vs 89.3 pg/ml, p< 0.05; IL-8: MSU 2896 vs 9781 pg/ml; CPP 3984 vs 6820 pg/ml, p< 0.01).

Conclusion: Intermittent fasting alleviates crystal-induced inflammation by altering many metabolic pathways, particularly those associated with glutamine and glutamate. Further studies are needed to determine how crystals modulate metabolism and potential anti-inflammatory effects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intermittent-fasting-reduces-crystal-induced-inflammation/