Pentagalloyl glucose inhibits monosodium urate-induced inflammation and NLRP3 inflammasome formation via TAK1.

Abstract

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 which 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 TAK1^184/187 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, 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 which were reduced to only 139 by PGG and 132 by 5Z7o. Administration of PGG (30 mg/kg; intraperitoneally) 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.