Monosodium urate (MSU)-induced inflammation is caused by the deposition of MSU crystals in the joints and periarticular tissues under conditions of hyperuricemia. These deposits can activate joint resident macrophages that form the NOD-, LRR-, and pyrin-containing protein 3 (NLRP3) inflammasome, cleaving pro-IL-1β and causing inflammation. The present study investigated the anti-inflammatory properties of a polyphenolic compound pentagalloyl glucose (PGG) in MSU-induced inflammation. Pretreatment of THP-1 monocyte-derived macrophages with PGG (0.1-10 µM) caused a dose-dependent inhibition of MSU-induced TAK1184/187 and NF-κB p65 phosphorylation. PGG significantly reduced the production of pro-IL-1β during the priming phase, which correlated with its inhibition of NLRP3 inflammasome formation as observed by the reduced ASC speck formation and a consequent decrease in IL-8, monocyte chemoattractant protein (MCP-1), and IL-1β production. Using liquid chromatography/mass spectrometry (LC-MS/MS)-based untargeted phosphoproteomics analysis, we discovered 3,919 unique phosphorylation sites modulated by MSU. Of 667 phosphosites upregulated by MSU, PGG selectively suppressed 218, a TAK1 inhibitor (5Z-7-oxozeaenol; 5Z7o) inhibited 134, and both inhibitors commonly inhibited 181. Conversely, 443 total phosphosites were suppressed by MSU that were reduced to only 139 by PGG and 132 by 5Z7o. Administration of PGG (30 mg/kg ip) significantly suppressed MSU-induced paw inflammation in C57BL/6J mice and reduced the time to flare resolution. These findings showed that PGG significantly reduced MSU-induced proinflammatory mediators and inhibited the formation of NLRP3 inflammasomes by primarily targeting the TAK1 pathway. Our finding suggests that dietary supplementation of PGG may help reduce the onset and severity of acute gout flares.NEW & NOTEWORTHY Current treatment options for the management of pain and inflammation in gout are inadequate and expensive. Our study provides a novel mechanism for regulating inflammasome formation and gout flares by a natural polyphenol, pentagalloyl glucose (PGG), that is found in fruits and vegetables. PGG also inhibits xanthine oxidase activity, an enzyme that produces uric acid that contributes to monosodium urate crystal formation, making it a dual inhibitor to be further tested in treating gout.
Keywords: NLRP3 Inflammasome; TAK1; gout; interleukin-1; pentagalloyl glucose.